Free ASCP MLS Exam Practice Questions Mock Test: Part 31 – Immunology – Transplantation

• Hyperacute rejection is primarily mediated by pre-existing antibodies in the recipient that bind to antigens (e.g., ABO or HLA) on the donor endothelium (lining of blood vessels). This triggers rapid complement activation, thrombosis, and graft destruction within minutes to hours.

• Acute rejection (a) is mainly T cell–mediated, though antibodies can contribute in some cases.

• Chronic rejection (c) involves both antibodies and T cells, leading to fibrosis and vascular damage over time, but it is not driven solely by immediate antibody binding.

• Antibody-mediated rejection is a key feature of hyperacute rejection, making option (d) incorrect.

• Azathioprine is an antimetabolite immunosuppressive drug. It is metabolized to 6-mercaptopurine, which inhibits purine synthesis and interferes with DNA and RNA production. This suppresses the proliferation of rapidly dividing cells, including T and B lymphocytes, thereby reducing the immune response.

• Cyclosporine (b) and tacrolimus (c) are calcineurin inhibitors that block T-cell activation by inhibiting IL-2 production.

• Prednisone (d) is a corticosteroid that suppresses inflammation and immune responses through broad anti-inflammatory effects and cytokine inhibition.

• An allograft (also called an allogeneic graft) is a transplant between genetically non-identical members of the same species. This is the most common type of graft in human organ transplantation (e.g., a kidney from a donor to a recipient who is not an identical twin).

• Autograft (a) is a graft within the same individual (e.g., skin graft), but it is not used for organ transplantation.

• Xenograft (c) is a transplant from a different species (e.g., pig heart to human) and is experimental and rare.

• Isograft (d) is a transplant between genetically identical individuals (e.g., identical twins), which is very uncommon due

• Graft-versus-host disease (GVHD) is the major complication of bone marrow transplantation (or hematopoietic stem cell transplantation). It occurs when immunocompetent T cells from the donor marrow recognize the recipient’s tissues as foreign and mount an immune attack. This can affect the skin, liver, gastrointestinal tract, and other organs, leading to significant morbidity and mortality.

• While graft rejection (a) can occur (where the recipient’s immune system rejects the donor marrow), it is less common with modern conditioning regimens.

• Hyperacute rejection (c) and ABO incompatibility (d) are more relevant to solid organ transplants (e.g., kidney or heart) and are not typical issues in bone marrow transplantation. ABO mismatches can cause hemolysis but are manageable and not the primary complication.

• Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine strongly associated with graft rejection–related inflammation. It is produced by activated macrophages, T cells, and other immune cells during rejection and contributes to:

  • Endothelial activation and vascular permeability.

  • Recruitment of inflammatory cells (e.g., neutrophils, lymphocytes) to the graft.

  • Direct tissue injury and promotion of fibrosis in chronic rejection.

• Other options:

  • a) IL-4: Involved in Th2 responses and antibody production but not primarily pro-inflammatory in rejection.

  • c) IL-5: Promotes eosinophil activation and is linked to allergies/parasitic infections, not graft rejection.

  • d) IL-10: An anti-inflammatory cytokine that suppresses immune responses and may mitigate rejection.

• Hyperacute rejection occurs within minutes to hours after transplantation due to pre-existing antibodies in the recipient against donor antigens (e.g., ABO blood group antigens or HLA antigens).

• Cross-matching is a critical pre-transplant test where the recipient’s serum is screened for antibodies against donor lymphocytes. A negative cross-match indicates no pre-formed antibodies and prevents hyperacute rejection.

• High-dose steroids (b) are used to treat acute rejection but cannot prevent hyperacute rejection once it starts.

• Suppressing T cells only (c) is ineffective because hyperacute rejection is antibody-mediated (humoral).

• Xenografts (d) (transplants between species) actually carry a higher risk of hyperacute rejection due to strong species-specific antibody responses.

• Xenotransplantation (e.g., using pig organs for humans) faces the major barrier of hyperacute rejection, which occurs within minutes to hours. This is primarily due to pre-existing natural antibodies in humans that recognize xenogeneic antigens, such as α-1,3-galactose (α-Gal) on pig cells. These antibodies activate the complement system, leading to rapid thrombosis and graft destruction.

• While other factors like organ size (a), HLA mismatches (c), and organ lifespan (d) can be concerns, they are secondary to the immediate immune barrier of hyperacute rejection. For example:

  • a): Pig organs can be sized appropriately through breeding or genetic engineering (e.g., pigs grown to human proportions).

  • c): HLA matching is not relevant across species, but overcoming species-specific antigen barriers (like α-Gal) is more critical.

  • d): Long-term graft function is possible if rejection is controlled.

• Graft-versus-host disease (GVHD) occurs when immunocompetent T cells from the donor graft (e.g., in a bone marrow or stem cell transplant) recognize the recipient’s tissues as foreign and mount an immune attack. This is initiated by the donor’s immune cells against the host’s antigens.

• It is not initiated by the recipient (a), as the recipient’s immune system is typically suppressed prior to transplantation.

• GVHD is a major concern in bone marrow transplants (b), often causing severe complications affecting the skin, liver, and gastrointestinal tract.

• It is not asymptomatic (c); acute GVHD can cause rash, diarrhea, jaundice, and chronic GVHD leads to fibrosis and organ dysfunction.

• Natural Killer (NK) cells play a role in transplantation through their ability to detect and eliminate cells that lack or downregulate self MHC class I molecules (a phenomenon known as “missing self” recognition). In the context of transplantation:

  • Donor cells (e.g., in an allograft) may have mismatched MHC class I molecules or may downregulate MHC due to stress/inflammation, making them targets for NK cell-mediated killing.

  • NK cells contribute to graft rejection by directly lysing donor cells and producing inflammatory cytokines (e.g., IFN-γ) that enhance immune responses.

• Other options are incorrect:

  • a): NK cells are not the primary initiators of graft-versus-host disease (GVHD); T cells from the donor are responsible.

  • c): NK cells do not produce antibodies; B cells and plasma cells do.

  • d): NK cells are involved in rejection, particularly in cases where T-cell responses are suppressed or in xenotransplantation.

• Tacrolimus and cyclosporine are calcineurin inhibitors with a narrow therapeutic window, meaning their levels must be carefully monitored to ensure they are effective without being toxic.

• Trough levels (the lowest concentration in the blood, typically measured just before the next dose) are crucial for:

  • Preventing rejection: Subtherapeutic levels may lead to inadequate immunosuppression and rejection.

  • Avoiding toxicity: High levels can cause kidney damage, neurotoxicity, hypertension, or diabetes.

• Other options:

  • a) CBC: Monitors for side effects like anemia or leukopenia but not drug levels.

  • b) Serum creatinine: Assesses kidney function (a key toxicity of calcineurin inhibitors) but is not a direct measure of drug exposure.

  • d) Liver function tests: Screens for hepatotoxicity but does not reflect immunosuppressive efficacy.

• CD8+ cytotoxic T cells are the primary immune cells that directly mediate graft tissue destruction during rejection. They recognize donor MHC class I antigens on graft cells and initiate killing through:

  • Perforin and granzyme release, which induces apoptosis in target cells.

  • Fas-Fas ligand interactions, triggering programmed cell death.

• This direct cytotoxicity is a hallmark of acute cellular rejection.

• Other options:

  • b) B cells: Produce antibodies that contribute to antibody-mediated rejection but are not directly cytotoxic.

  • c) Mast cells: Involved in allergic responses and inflammation but not direct graft destruction.

  • d) Plasma cells: Differentiated B cells that secrete antibodies but lack cytotoxic activity.

• An allograft (also called an allogeneic transplant) involves the transfer of an organ or tissue between genetically non-identical members of the same species. In this case, a kidney from an unrelated human donor to the recipient is an allograft.

• This is the most common type of organ transplant and requires immunosuppression to prevent rejection due to genetic differences (e.g., HLA mismatches).

Other options:

• Syngraft (b): Another term for isograft, which refers to a transplant between genetically identical individuals (e.g., identical twins).

• Autograft (c): A transplant within the same individual (e.g., moving skin from one area to another).

• Xenograft (d): A transplant between different species (e.g., pig kidney to human).

• An autograft involves transferring tissue (e.g., skin, bone, or blood vessels) from one site to another on the same individual. For example, a skin graft taken from a patient’s thigh to cover a burn wound on their arm is an autograft.

• Since the tissue is genetically identical to the recipient, there is no risk of immune rejection, and immunosuppression is not required.

Other options:

• a) Allograft: Transfer between genetically non-identical members of the same species (e.g., organ transplant from a donor to another person).

• b) Isograft (Syngraft): Transfer between genetically identical individuals (e.g., twins).

• d) Xenograft: Transfer between different species (e.g., pig heart to human).

• Hydrodynamic focusing is the technique used in flow cytometry to precisely center the sample core (containing cells or particles) within a surrounding sheath fluid. This creates a narrow, coaxial stream where cells pass single-file through the laser interrogation point, ensuring accurate and consistent measurements of light scattering and fluorescence.

• Acoustic focusing (a) uses sound waves to align cells but is less common and not standard in traditional flow cytometers.

• Liquid focusing (c) is not a standard term in flow cytometry.

• Isoelectric focusing (d) is an electrophoretic technique for separating proteins based on their isoelectric point, unrelated to flow cytometry.

• Isograft refers to a graft between genetically identical individuals, such as identical twins or members of the same inbred strain of animals.

• Autograft (a) is a graft from one part of the body to another in the same individual.

• Allograft (b) is a graft between genetically different individuals of the same species.

• Xenograft (d) is a graft between individuals of different species.

• Hyperacute rejection occurs within minutes to hours after transplantation and is driven by pre-existing antibodies in the recipient against donor antigens, such as MHC antigens (HLA) on white blood cells or endothelial cells. This triggers rapid complement activation, thrombosis, and graft destruction.

• This is distinct from chronic cell-mediated rejection, which develops over months to years and involves:

  • a) Narrowing and occlusion of graft blood vessels (due to fibrosis and smooth muscle proliferation).

  • b) Reaction of T and B cells to graft antigens (leading to chronic inflammation and antibody-mediated damage).

  • d) Arteriosclerosis of the graft arterial wall (a hallmark of chronic rejection, often called transplant vasculopathy).

• The direct pathway of allorecognition occurs when recipient T cells directly recognize intact donor Major Histocompatibility Complex (MHC) molecules (e.g., HLA molecules) on the surface of donor antigen-presenting cells (APCs). This is a potent mechanism in early graft rejection, as a large number of recipient T cells can cross-react with donor MHC molecules.

• This contrasts with the indirect pathway, where recipient APCs process and present donor-derived peptides on self-MHC molecules to T cells.

• Option (b) involves antibody-mediated recognition (humoral response), not direct T cell allorecognition.

• Option (c) describes graft-versus-host disease (GVHD), where donor T cells attack host tissues.

• Option (d) refers to immunosuppressive mechanisms (e.g., cytokine blockade), not allorecognition.

Antithymocyte Globulin (ATG) is a polyclonal antibody preparation that targets multiple antigens on human T lymphocytes. Its primary use is as induction therapy around the time of transplantation to rapidly deplete T cells, thereby reducing the risk of acute rejection in the early post-transplant period. It is also used to treat severe acute rejection episodes.

The other options are incorrect because:

• a) ATG is not used for long-term maintenance due to its potent side effects and risk of over-immunosuppression; it is typically used short-term.

• c) ATG does not treat viral infections like CMV; in fact, it increases the risk of infections due to its strong immunosuppressive effects.

• d) ATG does not stimulate bone marrow production; it is immunosuppressive and can sometimes cause bone marrow suppression as a side effect

• The graft-versus-leukemia (GVL) effect is a beneficial form of graft-versus-host (GVH) response where donor T cells from the bone marrow transplant recognize and destroy residual leukemia cells in the recipient. This reduces the risk of cancer relapse and is a key therapeutic goal in hematopoietic stem cell transplantation for hematologic malignancies (e.g., leukemia, lymphoma).

• While GVHD (damaging attack on host tissues) and GVL often occur together, strategies are used to maximize GVL while minimizing GVHD.

• Other options are incorrect:

  • a) Rejection of donor kidney: This is harmful transplant rejection, not beneficial.

  • c) Host immune system destroying donor liver: This is organ rejection, not a GVH effect.

  • d) Skin graft acceptance: Indicates tolerance, not a GVH effect.

• Anti-thymocyte globulin (ATG) is a polyclonal antibody therapy that depletes T cells from the recipient’s circulation before transplantation. It is commonly used as an induction agent to prevent acute rejection by reducing the number of alloreactive T cells that could attack the graft.

• Other options:

  • b) Prednisone: A corticosteroid that suppresses inflammation and immune responses broadly but does not specifically deplete T cells.

  • c) Cyclophosphamide: An alkylating agent that targets rapidly dividing cells (including lymphocytes) but is more commonly used in autoimmune diseases or cancer, not standard transplant induction.

  • d) Rituximab: Depletes B cells (via CD20 targeting) and is used for antibody-mediated rejection or desensitization, not T-cell depletion.

Sirolimus (Rapamycin) works by binding to the FKBP-12 protein, and this complex then inhibits the mammalian target of rapamycin (mTOR). mTOR is a key kinase involved in cell cycle progression and proliferation. By inhibiting mTOR, sirolimus blocks the response to interleukin-2 (IL-2) and other growth factors, preventing T-cell activation and proliferation. This makes it effective in preventing transplant rejection.

The other options are incorrect because:

• a) Inhibiting calcineurin is the mechanism of calcineurin inhibitors like cyclosporine and tacrolimus.

• b) Blocking purine synthesis is the mechanism of antimetabolites like azathioprine and mycophenolate.

• d) Depleting circulating T cells is the mechanism of lymphocyte-depleting antibodies like antithymocyte globulin (ATG) or alemtuzumab.

• Interleukin-2 (IL-2) is a critical cytokine for T-cell activation, proliferation, and differentiation. It is produced by activated T cells and promotes the expansion of antigen-specific T cells, including those targeting donor antigens in transplantation.

• IL-2 is a key target for immunosuppressive drugs such as:

  • Calcineurin inhibitors (e.g., cyclosporine, tacrolimus): Block IL-2 gene transcription.

  • mTOR inhibitors (e.g., sirolimus): Inhibit IL-2 receptor signaling.

• Other options:

  • b) IL-4: Involved in Th2 responses and B-cell activation (not a primary T-cell activator).

  • c) IL-10: An anti-inflammatory cytokine that suppresses immune responses.

  • d) IFN-γ: Promotes macrophage activation and Th1 responses but is not the central T-cell growth factor like IL-2.

• The direct pathway of allorecognition occurs when recipient T cells directly recognize intact donor MHC molecules (class I or II) on the surface of donor antigen-presenting cells (APCs). This is a potent mechanism because a large proportion of recipient T cells can cross-react with donor MHC-peptide complexes, leading to strong T-cell activation and rapid graft rejection.

• This contrasts with the indirect pathway (option b), where recipient APCs process donor antigens and present them as peptides on self-MHC molecules to T cells.

• Options a and d are incorrect:

  • a): Involves self-recognition, not allorecognition.

  • d): Describes a scenario where donor APCs present donor peptides, but recipient T cells would still recognize intact donor MHC (direct pathway), not just the peptides.

• For bone marrow transplantation (or hematopoietic stem cell transplantation), matching at the HLA-DR locus (a Class II MHC molecule) is considered the most critical to prevent graft rejection and graft-versus-host disease (GVHD).

  • HLA-DR disparities are strongly associated with increased risks of GVHD and graft failure.

  • While matching at other loci (HLA-A, HLA-B, HLA-C) is also important, HLA-DR matching has the greatest impact on outcomes.

• Why not the others?

  • a) HLA-A and b) HLA-B (Class I): Important for cytotoxic T-cell responses and GVHD but secondary to HLA-DR.

  • d) HLA-C: Plays a role in NK cell recognition (via KIR interactions) and GVHD but is less prioritized than HLA-DR.

Graft-versus-host disease (GVHD) is a complication primarily seen in bone marrow or stem cell transplantation, where immunocompetent donor T cells within the graft recognize the recipient’s (host’s) tissues as foreign and mount an immune attack.

• Other options are incorrect:

  • a) Donor antibodies: GVHD is primarily T cell-mediated, though antibodies may play a minor role in chronic GVHD.

  • c) Host NK cells: These are part of the host’s immune system and may contribute to graft rejection, not GVHD.

  • d) Complement overactivation: This is characteristic of hyperacute rejection in solid organ transplants, not GVHD.

• The primary goal of immunosuppressive drugs after transplantation is to suppress the recipient’s immune system to prevent it from recognizing and attacking the donor organ as foreign. This mitigates the risk of acute and chronic rejection, allowing the graft to survive and function.

• These drugs do not cure the original disease (a), stimulate organ growth (c), or increase red blood cell production (d). Instead, they specifically target immune pathways (e.g., T-cell activation, cytokine production) to induce a state of controlled immune tolerance.

• An allograft (also called an allogeneic transplant) involves the transfer of cells, tissues, or organs between genetically unrelated members of the same species. For example, a kidney transplant from a donor to a recipient who is not a relative (or is a relative but not genetically identical) is an allograft.

• This is the most common type of transplant in humans and carries a risk of rejection due to genetic differences.

Other options:

• Autograft (a): Transfer within the same individual (e.g., skin graft from thigh to arm).

• Isograft (c): Transfer between genetically identical individuals (e.g., identical twins).

• Xenograft (d): Transfer between different species (e.g., pig heart to human).

• An autograft involves transplanting tissue from one part of a person’s body to another part of the same individual. In this case, the skin is taken from the patient’s thigh and grafted onto their arm, which is a classic example of an autograft.

• This type of graft avoids immune rejection since the tissue is genetically identical to the recipient’s own tissue.

Other options:

• Isograft (a): Between genetically identical individuals (e.g., identical twins), not applicable here.

• Xenograft (b): Between different species (e.g., pig skin to human), not involved.

• Allograft (c): Between genetically different members of the same species (e.g., donor skin to recipient), not used here as the patient is their own donor.

• Chronic rejection is characterized by progressive graft dysfunction, fibrosis, and vascular damage (e.g., atherosclerosis of graft blood vessels). The main effector cells include:

  • CD8+ T cells: These cytotoxic T cells directly attack graft cells and contribute to tissue injury.

  • Macrophages: These cells promote chronic inflammation, fibrosis, and vascular remodeling through cytokine release (e.g., TGF-β) and tissue repair processes that become maladaptive.

• While other immune cells (e.g., antibodies, CD4+ T cells) also play roles, the sustained presence of CD8+ T cells and macrophages drives the fibrotic and obstructive changes in chronic rejection.

• Neutrophils (b) are involved in acute inflammation but not primarily in chronic rejection.

• Eosinophils (c) and mast cells (d) are associated with allergic responses and parasitic infections, not chronic transplant rejection.

• The indirect pathway of allorecognition occurs when recipient antigen-presenting cells (APCs) (such as dendritic cells) phagocytose donor graft cells, process the donor antigens (e.g., HLA peptides), and present them on recipient (self) MHC molecules to recipient T cells. This activates T cells indirectly, leading to an immune response against the graft.

• This differs from the direct pathway (where recipient T cells recognize intact donor MHC on donor APCs) and is particularly important in chronic rejection.

• Option (a) describes a mechanism in graft-versus-host disease (GVHD), not indirect allorecognition.

• Option (c) involves natural killer (NK) cells, which are part of innate immunity and not specific to the indirect pathway.

• Option (d) relates to antibody-mediated complement activation (e.g., in hyperacute rejection), which is not tied to indirect allorecognition.

• Graft-versus-host disease (GVHD) is primarily driven by mature donor T lymphocytes (from the graft) that recognize the recipient’s (host’s) tissues as foreign due to differences in major histocompatibility complex (MHC) or minor histocompatibility antigens. This triggers an immune response where donor T cells proliferate and attack host organs, such as the skin, liver, and gastrointestinal tract.

• It is not caused by host antibodies (a), donor NK cells attacking graft tissue (c), or host neutrophils (d). While other immune cells may contribute, the core mechanism involves donor T cell activation against host antigens.

Basiliximab is a monoclonal antibody that specifically binds to the CD25 subunit (the alpha chain) of the interleukin-2 (IL-2) receptor on the surface of activated T lymphocytes. By blocking this receptor, it prevents T cells from responding to IL-2, a critical cytokine for T-cell proliferation and immune response, thereby inducing immunosuppression. It is used for induction therapy to prevent acute rejection in organ transplantation.

The other options are incorrect because:

• a) Tacrolimus is a calcineurin inhibitor that inhibits T-cell activation by preventing IL-2 gene transcription.

• c) Azathioprine is an antimetabolite that inhibits purine synthesis, preventing lymphocyte proliferation.

• d) Sirolimus (rapamycin) is an mTOR inhibitor that blocks the response to IL-2, inhibiting T-cell proliferation.

• Xenograft (transplant between different species, e.g., pig organ to human) carries the highest risk of immunologic rejection due to:

  • Strong genetic disparity: Major differences in antigens (e.g., galactose-α-1,3-galactose [α-Gal] in pigs) trigger potent immune responses.

  • Pre-existing natural antibodies: Humans have antibodies against xenoantigens (e.g., anti-α-Gal IgM/IgG), leading to immediate hyperacute rejection.

  • Complement activation and inflammation: Rapid and severe immune reactions occur beyond what is seen in allografts.

• Other options:

  • a) Autograft (within the same individual): No risk of rejection (genetically identical).

  • b) Isograft (between genetically identical individuals, e.g., twins): Minimal to no risk of rejection.

  • d) Allograft (between non-identical members of the same species): Significant rejection risk but lower than xenografts due to closer genetic similarity.

The major histocompatibility complex (MHC), known as human leukocyte antigen (HLA) in humans, plays a central role in transplantation by presenting antigenic peptides to T cells. This process enables T cells to recognize self vs. non-self

• Other options are incorrect:

  • a): Immunosuppressive drugs (e.g., calcineurin inhibitors) target T-cell activation pathways, not MHC directly.

  • c): MHC does not produce antibodies; B cells/plasma cells do.

  • d): Erythropoietin (from kidneys) stimulates red blood cell production, not MHC.

• Cyclosporine specifically inhibits the calcineurin pathway. It binds to cyclophilin (a cytoplasmic protein), and this complex inhibits the enzyme calcineurin. Calcineurin is responsible for dephosphorylating NFAT (Nuclear Factor of Activated T-cells), which is necessary for the transcription of interleukin-2 (IL-2) and other T-cell activation genes. By blocking this pathway, cyclosporine prevents T-cell activation and proliferation.

• Other options:

  • a) Azathioprine: An antimetabolite that inhibits purine synthesis, affecting DNA replication and lymphocyte proliferation.

  • c) Sirolimus (Rapamycin): Binds to FKBP-12 and inhibits mTOR (mammalian Target of Rapamycin), blocking IL-2 receptor signaling and T-cell cycle progression. It does not inhibit calcineurin.

  • d) Mycophenolate mofetil: Inhibits inosine monophosphate dehydrogenase (IMPDH), blocking purine synthesis and preferentially affecting lymphocyte proliferation.

• T cells are primarily responsible for the direct recognition of donor MHC molecules in acute rejection. This occurs via the direct pathway of allorecognition, where recipient T cells recognize intact donor MHC molecules (class I or II) on the surface of donor antigen-presenting cells (APCs). This triggers a robust T-cell response, leading to graft attack.

• Other options:

  • a) B cells: Produce antibodies but do not directly recognize MHC molecules; they require T-cell help for activation.

  • b) Neutrophils: Involved in innate inflammation but not specific recognition of MHC.

  • d) NK cells: Recognize “missing self” (reduced MHC class I) but are not the primary cells for direct MHC recognition in acute rejection.

• CD8+ cytotoxic T cells are the primary effector cells in graft rejection. They directly recognize and kill donor cells (e.g., parenchymal cells or endothelium) through mechanisms like perforin/granzyme release and Fas-FasL interactions, leading to tissue destruction.

• CD4+ helper T cells (a) are crucial for activating and sustaining immune responses (e.g., by promoting CD8+ T cell function and antibody production), but they are not the direct killers.

• Regulatory T cells (c) suppress immune responses and promote tolerance, opposing rejection.

• NK T cells (d) bridge innate and adaptive immunity but are not the central players in rejection.

• Progressive fibrosis (scarring) of the graft’s tissues.

• Intimal hyperplasia and atherosclerosis-like narrowing of the blood vessels (often called graft arteriosclerosis), which is a hallmark feature.

• Gradual loss of organ function.

The other options are incorrect because:

• a) Occurring within hours describes hyperacute rejection.

• b) Being mediated by neutrophils and complement is characteristic of hyperacute and some forms of acute antibody-mediated rejection.

• d) It is not easily reversible with steroids. Chronic rejection is resistant to current immunosuppressive therapies and is a major cause of long-term graft failure

• The mixed lymphocyte reaction (MLC) is an in vitro test that measures the proliferative response of T cells from a potential recipient when exposed to donor lymphocytes. This proliferation occurs due to differences in HLA class II antigens (particularly HLA-DR, -DQ, -DP) on donor antigen-presenting cells.

  • A strong proliferative response indicates significant HLA class II disparity, predicting a higher risk of T-cell-mediated rejection.

  • The test primarily reflects CD4+ T cell activation via the indirect allorecognition pathway.

• Other options are incorrect:

  • a) ABO compatibility is assessed through blood typing, not MLC.

  • c) Pre-existing antibodies are detected via crossmatch tests or panel reactive antibody (PRA) assays.

  • d) Phagocytic function is evaluated through other specialized tests (e.g., neutrophil function assays).

• A xenograft (or xenotransplant) is a graft transplanted between individuals of different species (e.g., from a pig to a human).

• Autograft (a) is a graft within the same individual.

• Allograft (c) is a graft between genetically different individuals of the same species.

• Isograft (d) is a graft between genetically identical individuals (e.g., identical twins).

• Human Leukocyte Antigens (HLA) class I and II are the most critical histocompatibility complex molecules in transplantation. These molecules present antigens to T cells and are the primary targets of the immune response against grafts.

  • HLA class I (expressed on almost all nucleated cells) is recognized by CD8+ T cells.

  • HLA class II (expressed on antigen-presenting cells) is recognized by CD4+ T cells.

• Mismatches in HLA between donor and recipient can lead to acute and chronic rejection.

• ABO blood group antigens (b) are important for preventing hyperacute rejection but are not part of the major histocompatibility complex (MHC).

• CD markers (c) are cell surface molecules used to identify immune cells (e.g., CD4, CD8) but are not directly involved in graft antigen recognition.

• TCR molecules (d) are T cell receptors that recognize HLA antigens but are not the histocompatibility molecules themselves.

• HLA-B8 is a human leukocyte antigen (HLA) class I molecule that has been associated with an increased incidence of certain autoimmune diseases. Specifically:

  • Myasthenia gravis: HLA-B8 is linked to an increased risk, particularly in early-onset cases.

  • Celiac disease: HLA-B8 (along with HLA-DR3 and HLA-DQ2) is strongly associated with susceptibility to celiac disease.

• Other options are incorrect:

  • Ankylosing spondylitis (a, b) is primarily associated with HLA-B27, not HLA-B8.

  • Reiter disease (d) (reactive arthritis) is also linked to HLA-B27, not HLA-B8.

  • Multiple sclerosis (d) is associated with HLA-DR2 (DRB1*1501), not HLA-B8.

• Chronic rejection is a slow, progressive process that occurs over months to years post-transplant. Its hallmark histological features include:

  • Vascular occlusion: Due to intimal hyperplasia (proliferation of smooth muscle cells) and atherosclerosis-like changes in graft arteries.

  • Fibrosis: Excessive deposition of collagen and scar tissue, leading to parenchymal destruction and loss of organ function (e.g., tubular atrophy in kidneys, bronchiolitis obliterans in lungs).

• These changes result from chronic immune-mediated injury (both T-cell and antibody-driven) and non-immune factors (e.g., ischemia, drug toxicity).

• Other options are incorrect:

  • a) Massive infiltration of neutrophils: Characteristic of acute inflammation or hyperacute rejection, not chronic rejection.

  • c) Deposition of immune complexes in glomeruli: Seen in conditions like lupus nephritis but not specific to chronic transplant rejection.

  • d) Hemorrhage and thrombosis: Typical of hyperacute or acute antibody-mediated rejection.

The most significant risk factor for developing post-transplant lymphoproliferative disorder (PTLD) is Epstein-Barr virus (EBV) infection. PTLD is a spectrum of lymphoid proliferations that range from benign hyperplasia to malignant lymphomas, and it is strongly associated with immunosuppression. EBV-naïve recipients who receive an organ from an EBV-seropositive donor are at the highest risk. The immunosuppressive drugs impair T-cell function, which normally keeps EBV-infected B cells under control, leading to uncontrolled B-cell proliferation.

The other options are incorrect because:

• a) Hypertension, c) Diabetes mellitus, and d) Hyperlipidemia are common complications after transplantation, often related to immunosuppressive therapy (e.g., calcineurin inhibitors like cyclosporine or tacrolimus), but they are not direct risk factors for PTLD.

Hyperacute rejection occurs within minutes to hours after transplantation and is primarily mediated by pre-existing antibodies in the recipient that are directed against donor antigens, such as ABO blood group antigens or human leukocyte antigens (HLA). These antibodies activate the complement system, leading to rapid thrombosis, endothelial damage, and graft failure. This type of rejection is usually prevented by ensuring ABO compatibility and performing cross-match tests to detect pre-formed anti-donor antibodies before transplantation.

• Option a) (mismatch in minor histocompatibility antigens) typically leads to acute or chronic rejection, not hyperacute.

• Option b) (pre-existing cytotoxic T cells) is more associated with acute cellular rejection, which occurs days to weeks post-transplant.

• Option d) (overwhelming bacterial infection) is not a direct cause of hyperacute rejection, though infections can complicate transplantation.

• Hyperacute rejection is driven by pre-existing antibodies (against ABO or HLA antigens) binding to the donor endothelium. This activates the complement cascade via the classical pathway.

• C3b is a central complement component that opsonizes the graft endothelium, promotes inflammation, and leads to membrane attack complex (MAC) formation (involving C9), resulting in rapid endothelial damage and thrombosis.

• While other components like C1q (a, initiates classical pathway), C5a (c, anaphylatoxin), and C9 (d, part of MAC) are involved, C3b is particularly critical as it amplifies the complement response and bridges opsonization to MAC formation.

• Histocompatibility refers to the similarity of human leukocyte antigens (HLA) and other antigens between the donor and recipient. This is the most critical factor in transplant success because:

  • Close HLA matching reduces the risk of immune recognition and rejection (both acute and chronic).

  • It minimizes the need for intense immunosuppression, lowering complications like infections and malignancies.

• While other factors (e.g., donor age, organ quality, surgical technique) influence outcomes, histocompatibility is the primary determinant of long-term graft survival.

• Other options are incorrect:

  • a) Donor age: Affects organ viability (e.g., older donors may have reduced function) but is secondary to HLA matching.

  • b) Organ color: Not a relevant factor; organ appearance may indicate ischemia or damage but does not predict success.

  • d) Surgeon’s blood type: Has no biological impact on graft acceptance.

• The earliest signs of acute rejection in kidney transplantation often include fever, graft tenderness (pain over the transplant site), and decreased urine output. These symptoms typically occur days to weeks after transplantation and reflect immune-mediated inflammation targeting the graft.

• Additional signs may include rising serum creatinine (indicating impaired kidney function) and hypertension.

• Fibrosis (b) is a feature of chronic rejection, developing over months to years.

• Rapid necrosis within minutes (c) characterizes hyperacute rejection, not acute rejection.

• While rejection can sometimes be asymptomatic initially (d), clinical symptoms like fever and tenderness are common early indicators that prompt further diagnostic testing (e.g., biopsy).

• For bone marrow transplants (or hematopoietic stem cell transplants), matching the Human Leukocyte Antigen (HLA) system is critically important. HLA antigens (especially HLA-A, HLA-B, HLA-C, and HLA-DR) are the primary determinants of immune compatibility between donor and recipient.

  • Close HLA matching minimizes the risk of graft rejection (where the recipient’s immune system attacks the donor cells) and graft-versus-host disease (GVHD) (where donor immune cells attack the recipient’s tissues).

• While ABO-Rh compatibility (a) is considered and can prevent issues like hemolysis, it is not an absolute requirement and can be managed through processing of the graft or plasma exchange. HLA matching takes precedence.

• CD4/CD8 (c) refers to T-cell markers, not an antigen system for matching donors and recipients.

• Pi²⁺ (d) is not a standard antigen system in transplantation; it may refer to other biological markers (e.g., PiMZ for alpha-1 antitrypsin deficiency), but it is irrelevant to donor-recipient matching for bone marrow transplants.

• Skin grafts are considered the most immunogenic type of transplant due to several factors:

  • High antigen density: Skin contains abundant HLA class I and II antigens, Langerhans cells (dendritic cells), and other immune-activating molecules.

  • Strong T-cell response: Skin grafts provoke a potent adaptive immune response, leading to rapid rejection without immunosuppression.

  • Clinical observation: Even with HLA matching, skin grafts require intense immunosuppression to survive, unlike some organs.

• Other options:

  • a) Kidney: Immunogenic but less than skin; kidneys can tolerate some mismatch with immunosuppression.

  • b) Heart: Highly immunogenic but still less than skin due to lower antigen presentation.

  • d) Liver: Considered immunoprivileged; it has lower rejection rates due to regenerative capacity and tolerogenic properties (e.g., production of soluble HLA antigens).

• The liver is known to have a lower risk of rejection compared to other organs like the kidney, heart, or lung. This is due to its unique immunologic properties, including:

  • Regenerative capacity: The liver can repair itself and tolerate some immune damage.

  • Immune tolerance: The liver produces soluble HLA antigens that may neutralize antibodies and modulate the immune response.

  • Microchimerism: Liver transplants often lead to the exchange of immune cells between donor and recipient, promoting tolerance.

• Kidney (a), heart (c), and lung (d) transplants generally require stronger or more prolonged immunosuppression due to higher rejection rates. For example, lungs have the highest rejection rates among solid organ transplants.

• Tacrolimus (also known as FK506) binds to FK506-binding protein (FKBP) in T cells. This complex then inhibits the enzyme calcineurin, which is critical for the activation of nuclear factor of activated T cells (NFAT). NFAT is a transcription factor that promotes the expression of interleukin-2 (IL-2) and other T cell activation genes. By inhibiting calcineurin, tacrolimus effectively suppresses T cell activation and proliferation.

• Cyclosporine (a) also inhibits calcineurin but binds to a different cytoplasmic protein (cyclophilin).

• Prednisone (c) is a corticosteroid that broadly suppresses inflammation and immune responses but does not target FKBP or calcineurin.

• Azathioprine (d) is an antimetabolite that interferes with DNA synthesis and purine metabolism, not T cell signaling via FKBP.

• The scenario describes gradual loss of organ function over a long period (10 years post-transplant) with a biopsy showing fibrous scarring. This is classic for chronic rejection, which is characterized by:

  • Progressive fibrosis (scar tissue deposition).

  • Vascular changes (e.g., intimal hyperplasia, arterial narrowing).

  • Gradual deterioration of graft function due to persistent immune-mediated injury (both T-cell and antibody-driven) and non-immune factors (e.g., calcineurin inhibitor toxicity, ischemia).

• Other options:

  • a) Successful graft acceptance: Would show normal histology and function, not scarring or dysfunction.

  • b) Acute antibody-mediated rejection: Occurs early post-transplant (days to weeks) with sudden dysfunction, C4d staining, and inflammation—not gradual fibrosis.

  • d) An infectious complication: Might cause inflammation or specific pathogen-related changes (e.g., viral inclusions), but not typically isolated fibrous scarring.

• Acute cellular rejection is primarily driven by CD8+ cytotoxic T cells, which directly recognize and kill donor cells (e.g., graft parenchymal cells or endothelial cells) via perforin/granzyme pathways or Fas-FasL interactions.

• CD4+ T helper cells (a) play a crucial role by promoting inflammation, activating CD8+ T cells, and supporting antibody production, but they are not the direct effectors of cellular destruction.

• Regulatory T cells (Tregs) (c) suppress immune responses and promote tolerance, opposing rejection.

• Gamma-delta T cells (d) are involved in innate-like immunity and tissue surveillance but are not the primary mediators of acute rejection.

• Chronic rejection is the most difficult to prevent with current immunosuppressive therapies. It develops gradually over months to years and involves both immune-mediated mechanisms (e.g., antibodies, T-cells) and non-immune factors (e.g., ischemia, drug toxicity). Histologically, it is characterized by fibrosis, vascular occlusion, and parenchymal atrophy, leading to irreversible graft dysfunction.

• Immunosuppressants (e.g., calcineurin inhibitors) are effective against acute rejection but poorly halt the progressive scarring and vascular changes of chronic rejection.

• Other options:

  • a) Hyperacute rejection: Largely preventable with ABO compatibility and crossmatch testing; immunosuppression is not needed if preformed antibodies are avoided.

  • b) Acute rejection: Often controllable with intensified immunosuppression (e.g., steroids, antibody therapies).

  • d) GVHD: Manageable with immunosuppressants in many cases, though it remains a challenge in bone marrow transplants.

• Anti-HLA antibody testing (also known as panel reactive antibody (PRA) testing) is critical for the recipient but not for the donor. This test detects pre-existing antibodies in the recipient’s blood against HLA antigens, which could target the donor’s organ and cause hyperacute or accelerated rejection.

• Donors are not routinely screened for anti-HLA antibodies because their immune response is not the primary concern; the focus is on their HLA type and antigen compatibility with the recipient.

• Other procedures are relevant to both donor and recipient:

  • ABO typing (a): Essential for both to ensure blood group compatibility.

  • HLA typing (b): Performed on both to assess histocompatibility.

  • CMV testing (c): Important for both to assess cytomegalovirus status and guide post-transplant prophylaxis (as CMV can reactivate and cause disease post-transplant).

• An isograft (also known as a syngraft) is a transplant between genetically identical individuals, such as identical twins. Because the donor and recipient share identical genetic makeup, including HLA antigens, there is no risk of immune rejection, and immunosuppression is not required.

• Other options:

  • b) A graft from one species to another: This is a xenograft.

  • c) A graft from one site to another on the same individual: This is an autograft.

  • d) A graft between two unrelated individuals: This is an allograft.

• Basiliximab is a monoclonal antibody used prophylactically to prevent acute organ rejection in transplant recipients (e.g., kidney transplantation). It works by specifically binding to the IL-2 receptor (CD25) on the surface of activated T cells, blocking the interaction with interleukin-2 (IL-2). This inhibits T-cell proliferation and clonal expansion, thereby suppressing the immune response against the graft.

• It is typically used as part of an induction therapy regimen immediately post-transplant to provide intense initial immunosuppression.

• Other options are incorrect:

  • a): Basiliximab does not treat viral infections; it may actually increase infection risk due to immunosuppression.

  • c): It has no role in cholesterol management.

  • d): It suppresses rather than stimulates white blood cell production.

• Bone marrow transplantation requires strict ABO compatibility in addition to HLA matching because:

  • ABO incompatibility can cause hemolysis of donor or recipient red blood cells.

  • It can lead to complications such as delayed red cell engraftment or hemolytic reactions.

• For solid organ transplants (kidney, liver, heart):

  • ABO compatibility is preferred, but liver transplants can sometimes succeed across ABO barriers due to its tolerogenic properties.

Option breakdown:

• a) Kidney → ABO matching preferred, but HLA matching is more critical.

• b) Liver → more tolerant of ABO mismatch.

• c) Heart → ABO matching important, but less strict than bone marrow.

• d) Correct → bone marrow transplant requires strict ABO and HLA compatibility.

• Mycophenolate mofetil (MMF) is an immunosuppressive drug that inhibits inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo pathway of purine synthesis. Since lymphocytes (T and B cells) rely heavily on this pathway for proliferation, MMF selectively suppresses their activation and expansion, reducing the immune response against the graft.

• Other options are incorrect:

  • b): Blocks IL-2 receptor → Action of basiliximab/daclizumab (anti-CD25 antibodies).

  • c): Inhibits calcineurin → Mechanism of cyclosporine and tacrolimus.

  • d): Binds to mTOR → Mechanism of sirolimus (rapamycin) and everolimus.

Graft-versus-host disease (GVHD) is a common and serious complication of allogeneic hematopoietic stem cell transplantation. It occurs when donor-derived immune cells (particularly T cells) attack the recipient’s tissues.

The other options are incorrect because:

• a) Improved skin integrity: GVHD causes severe skin damage, not improvement.

• c) Enhanced immune function against pathogens: GVHD is associated with immunodeficiency, increasing the risk of infections.

• d) Increased production of red blood cells: GVHD does not stimulate erythropoiesis; it may contribute to cytopenias due to bone marrow suppression or autoimmune destruction.

• Sirolimus (also known as Rapamycin) blocks IL-2 receptor signaling by binding to the mTOR (mammalian target of rapamycin) protein. This inhibits the downstream signaling pathway of the IL-2 receptor, preventing T-cell proliferation and progression from the G1 to the S phase of the cell cycle.

• Tacrolimus (a) inhibits calcineurin (like cyclosporine), which prevents IL-2 production but does not directly block IL-2 receptor signaling.

• Cyclophosphamide (c) is an alkylating agent that suppresses immune cells by cross-linking DNA, but it does not specifically target IL-2 signaling.

• Prednisone (d) is a corticosteroid that broadly suppresses inflammation and immune responses by inhibiting cytokine gene expression, but it is not specific to IL-2 receptor signaling.

• T lymphocytes (T cells) are the primary mediators of graft rejection. They recognize foreign antigens from the graft through direct or indirect allorecognition, leading to cell-mediated immune responses that destroy the transplanted tissue.

• While other immune cells play roles:

  • B lymphocytes (c) produce antibodies that can contribute to rejection (e.g., in hyperacute rejection), but they are not the primary effectors.

  • NK cells (d) can participate in rejection through antibody-dependent cellular cytotoxicity (ADCC) or direct killing, but their role is secondary to T cells.

  • Neutrophils (a) are involved in inflammation but are not the key drivers of graft rejection.

Corticosteroids like Prednisone are used in transplant regimens primarily for their broad anti-inflammatory and immunosuppressive effects. They work by inhibiting the expression of multiple genes involved in the immune response, including those encoding cytokines (e.g., IL-1, IL-2, IL-6, TNF-α), chemokines, and adhesion molecules. This nonspecific action helps to suppress T-cell activation, proliferation, and migration, as well as the function of antigen-presenting cells and other immune cells. They are particularly effective in preventing and treating acute rejection episodes.

Why the other options are incorrect:

• b) Corticosteroids do not specifically target B-cell antibody production; other agents like rituximab (anti-CD20) or mycophenolate are more targeted for that purpose.

• c) Corticosteroids do not stimulate regulatory T cells; in fact, they can suppress various T-cell populations broadly.

• d) Corticosteroids do not prevent bacterial infections; instead, they increase the risk of infections due to their immunosuppressive effects.

• Long-term immunosuppressive therapy (e.g., with calcineurin inhibitors like cyclosporine or tacrolimus, antimetabolites, or corticosteroids) suppresses the immune system’s ability to surveil and destroy cancerous cells. This leads to an increased risk of malignancies, particularly:

  • Skin cancers (e.g., squamous cell carcinoma).

  • Post-transplant lymphoproliferative disorder (PTLD), often associated with Epstein-Barr virus (EBV).

  • Other virally linked cancers (e.g., Kaposi sarcoma).

• Other options are incorrect:

  • a): Immunosuppression increases susceptibility to infections (bacterial, viral, fungal).

  • c): It often impairs wound healing due to reduced inflammation and collagen synthesis.

  • d): It reduces vaccine efficacy because the immune system cannot mount a robust response.

• Acute rejection typically occurs days to weeks after transplantation and is primarily mediated by T lymphocytes. This type of rejection involves the recipient’s immune system recognizing the graft as foreign and mounting a cellular immune response against it.

• It is not caused by preformed antibodies (a), which characterize hyperacute rejection.

• It is not caused by a chronic low-level antibody response (c), which is associated with chronic rejection.

• It does not occur in autografts (d), as autografts are from the same individual and do not trigger an immune response.

Endomyocardial biopsy is historically considered the “gold standard” for monitoring rejection after heart transplantation. This invasive procedure involves obtaining small tissue samples from the heart muscle, which are then examined under a microscope for cellular infiltrates and other signs of acute cellular rejection or antibody-mediated rejection. While non-invasive methods are being developed and used more frequently, the biopsy remains the definitive diagnostic tool for detecting rejection.

The other options are incorrect because:

• a) Serial blood tests for HLA antibodies can help monitor for antibody-mediated rejection but are not sufficient alone to diagnose cellular rejection and are not the gold standard.

• c) Echocardiogram is a valuable non-invasive tool to assess heart function and may suggest rejection if dysfunction is present, but it cannot provide a definitive histological diagnosis.

• d) Serum creatinine levels are used to monitor kidney function, not heart function or rejection in heart transplant recipients.

• The liver is considered the most rejection-resistant organ due to its unique immunologic properties:

  • Regenerative capacity: The liver can repair itself after immune-mediated injury.

  • Tolerogenic environment: It produces soluble HLA class I antigens that may neutralize antibodies and modulate immune responses.

  • Microchimerism: Liver transplants often lead to the exchange of immune cells between donor and recipient, promoting tolerance.

• Other options:

  • a) Kidney: Vulnerable to rejection without immunosuppression.

  • c) Skin: Highly immunogenic and prone to rapid rejection.

  • d) Heart: Susceptible to acute and chronic rejection.

• Graft-versus-host disease (GVHD) occurs when immunocompetent T cells from the donor graft (the graft) recognize and attack the recipient’s tissues (the host). This is most common after allogeneic bone marrow transplants (or stem cell transplants) because the graft contains immune cells that can mount an attack against the host’s antigens.

• GVHD does not occur in autografts (a) (self-grafts) or isografts (c) (grafts from genetically identical twins), as there is no genetic disparity to trigger an immune response.

• GVHD is theoretically possible in xenografts (d), but it is extremely rare and not clinically common due to the greater barriers in xenotransplantation.

• Hyperacute rejection occurs within minutes to hours after transplantation due to pre-existing antibodies in the recipient against donor antigens. The most critical antigens involved are the ABO blood group antigens.

• ABO blood group typing is essential to ensure compatibility between donor and recipient. If the recipient has preformed antibodies against the donor’s ABO antigens (e.g., a type O recipient receiving a type A kidney), these antibodies will immediately attack the graft, leading to rapid rejection.

• Rh typing (b) is important for blood transfusions and pregnancy but not directly for organ transplantation hyperacute rejection.

• ELISA for IgE (c) is related to allergic reactions, not transplant rejection.

• ANA testing (d) is used to detect autoimmune diseases like lupus, not for transplant compatibility.

• The indirect pathway of allorecognition is initiated when recipient antigen-presenting cells (APCs), such as dendritic cells or macrophages, phagocytose and process donor antigens (e.g., from the graft). These APCs then present donor-derived peptides on recipient MHC molecules to recipient T cells. This activates T cells indirectly, leading to an immune response against the graft.

• This pathway is particularly important in chronic rejection, as it promotes sustained immune activation against donor antigens.

• Other options are incorrect:

  • a) Donor T cells: These are involved in graft-versus-host disease (GVHD), not the indirect pathway.

  • c) NK cells: Part of innate immunity and recognize “missing self” but do not initiate indirect allorecognition.

  • d) Mast cells: Involved in allergic responses and inflammation but not antigen presentation for indirect allorecognition.

Xenografts (grafts from a different species, e.g., pig to human) are most susceptible to hyperacute rejection. This is due to the presence of pre-existing natural antibodies in humans against carbohydrate antigens (e.g., α-1,3-galactose) expressed on the cells of non-primate species. These antibodies rapidly bind to the graft endothelium, activate the complement system, and cause immediate thrombosis and graft destruction within minutes to hours.

Why the other options are less susceptible:

• a) Autograft (graft from oneself) and b) Isograft (graft from an identical twin) are not immunogenic and do not trigger rejection.

• c) Allograft (graft from a genetically non-identical member of the same species) can experience hyperacute rejection, but only if there are pre-formed antibodies against donor HLA or ABO antigens. With modern screening (crossmatch testing), this is largely preventable.

• ABO blood group incompatibility is an absolute contraindication to allotransplantation (transplantation between genetically different members of the same species). This is because pre-existing natural antibodies against ABO antigens (e.g., anti-A or anti-B antibodies) can cause immediate hyperacute rejection, leading to rapid graft destruction via complement activation and thrombosis.

• ABO matching is mandatory for most organ transplants (e.g., kidney, heart) to prevent this catastrophic reaction.

Other procedures:

• MLC (a): Mixed lymphocyte culture tests for HLA compatibility and predicts T-cell responses, but it is not an absolute contraindication (though HLA mismatches increase rejection risk).

• HLA typing (b): Important for reducing rejection risk but not an absolute contraindication; transplants can proceed with HLA mismatches using immunosuppression.

• Rh typing (c): Not relevant to organ transplantation rejection; it is critical for blood transfusions and pregnancy but does not cause hyperacute rejection in grafts.

In the indirect pathway of allorecognition, recipient T cells recognize donor MHC antigens that have been processed and presented as peptides by the recipient’s own antigen-presenting cells (APCs). This is similar to how the immune system normally responds to foreign antigens. The recipient APCs phagocytose donor cell debris, process the donor MHC proteins into peptides, and present these peptides on their own MHC molecules to activate recipient T cells. This pathway is particularly important in chronic rejection.

The other options are incorrect because:

• a) Recognizing intact donor MHC molecules on donor cells describes the direct pathway of allorecognition.

• c) Recipient peptides presented by donor APCs is not a standard pathway in allorecognition and is not clinically significant in this context.

• d) Bacterial peptides on donor tissue is unrelated to allorecognition; it would be a response to infection, not transplantation.

• Regulatory T cells (Tregs), a subset of CD4+ T cells, play a critical role in maintaining immune homeostasis by suppressing effector T-cell responses and promoting tolerance to self-antigens and foreign antigens (e.g., donor alloantigens).

  • They achieve this through mechanisms such as secreting anti-inflammatory cytokines (e.g., IL-10, TGF-β), direct cell contact inhibition, and modulating antigen-presenting cell function.

• In transplantation, Tregs are key to preventing rejection and enabling long-term graft survival without excessive immunosuppression. Their dysfunction can lead to autoimmunity or graft failure.

Other options are incorrect:

• a): Tregs suppress, not initiate, rejection.

• b): They inhibit antibody production rather than promote it.

• d): Tregs downregulate macrophage activation and inflammation.

• In bone marrow transplantation (or hematopoietic stem cell transplantation), the primary immunologic complication is graft-versus-host disease (GVHD). This occurs when immunocompetent T cells from the donor marrow recognize the recipient’s tissues as foreign and mount an immune attack. GVHD can affect the skin, liver, gastrointestinal tract, and other organs, leading to significant morbidity and mortality.

• Other options:

  • a) Rejection of donor marrow: This can occur but is less common with modern conditioning regimens (e.g., chemotherapy/radiation to suppress the recipient’s immune system).

  • c) Chronic fibrosis: This may result from chronic GVHD but is not the primary risk itself.

  • d) ABO incompatibility: This can cause hemolysis but is manageable and not the main immunologic complication.

• Sirolimus (Rapamycin) is an mTOR inhibitor that blocks IL-2–mediated T cell proliferation.

• It is often used in combination with calcineurin inhibitors (e.g., cyclosporine or tacrolimus) to provide synergistic immunosuppression while potentially reducing calcineurin-induced nephrotoxicity.

Option breakdown:

• a) Azathioprine → antimetabolite, can be used but less common now; mainly replaced by mycophenolate.

• b) Correct → Sirolimus, commonly combined with calcineurin inhibitors.

• c) Methotrexate → mainly used in GVHD prophylaxis after bone marrow transplant.

• d) Rituximab → anti-CD20 monoclonal antibody, used for B cell depletion in certain cases, not routine combination with calcineurin inhibitors.

• Interleukin-2 (IL-2) is the central cytokine that drives T cell proliferation and clonal expansion during graft rejection. It is produced by activated CD4+ T cells and binds to the high-affinity IL-2 receptor (CD25) on T cells, promoting their growth and differentiation into effector cells.

• IL-2 is a key target for immunosuppressive drugs (e.g., calcineurin inhibitors like tacrolimus) to prevent rejection.

• Other options:

  • a) IL-1: Involved in inflammation and fever but not primary T cell proliferation.

  • c) IL-6: Promotes B cell differentiation and acute-phase responses, not direct T cell expansion.

  • d) IFN-γ: Activates macrophages and enhances antigen presentation but is not the primary T cell growth factor.

• The presentation of fever and organ dysfunction in a transplant recipient, along with a biopsy showing lymphocytic infiltration (typically T cells invading the graft parenchyma), is classic for acute cellular rejection. This type of rejection usually occurs days to weeks post-transplant and is primarily T-cell-mediated.

• Other options:

  • a) Hyperacute rejection: Occurs within minutes to hours due to preformed antibodies, characterized by thrombosis and necrosis (not lymphocytic infiltration).

  • c) Chronic rejection: Develops over months to years with fibrosis and vascular occlusion (not acute symptoms like fever).

  • d) Graft-versus-host disease (GVHD): Occurs in bone marrow transplant recipients, where donor immune cells attack host tissues (e.g., skin, liver, gut), not solid organ grafts.

• An autograft involves transplanting tissue from one part of an individual’s body to another part of the same individual (e.g., skin graft from thigh to arm). Since the tissue is genetically identical to the recipient, no immune rejection occurs.

• Isograft (d): Transplant between genetically identical individuals (e.g., identical twins) also avoids rejection but is less common than autografts.

• Allograft (a): Transplant between genetically non-identical members of the same species (e.g., human to human) carries a high risk of rejection due to HLA mismatches.

• Xenograft (c): Transplant between different species (e.g., pig to human) has the highest risk of rejection due to strong genetic disparities and pre-existing antibodies.

The graft-versus-leukemia (GVL) effect is a desirable immunologic phenomenon in allogeneic bone marrow or hematopoietic stem cell transplantation. Donor-derived immune cells (particularly T lymphocytes) recognize and attack residual malignant cells (e.g., leukemia cells) in the recipient, helping to prevent cancer relapse. This effect is closely associated with graft-versus-host disease (GVHD) but can occur independently.

The other options are incorrect because:

• a) While GVL is often linked to graft-versus-host disease (GVHD), causing GVHD is not the desired outcome; GVHD is a harmful complication.

• b) Rejecting the donor bone marrow would lead to graft failure, which is undesirable.

• c) Further suppressing the recipient’s immune system is not the goal of GVL; instead, GVL relies on the donor immune system’s activity.

• Plasmapheresis is a procedure used to remove plasma (which contains antibodies, including preformed anti-HLA or anti-ABO antibodies) from the recipient’s blood. This reduces the risk of antibody-mediated rejection (e.g., hyperacute or acute rejection) when a recipient has pre-existing antibodies against donor antigens.

• It is often combined with other therapies (e.g., intravenous immunoglobulin or immunosuppressive drugs) to prevent antibody rebound.

Other options are incorrect:

• a): Plasmapheresis does not increase T cells; it may indirectly affect immunity but is not used for that purpose.

• c): It does not stimulate regulatory B cells; instead, it reduces pathogenic antibodies.

• d): Crossmatching is a diagnostic test performed in the lab, not a function of plasmapheresis.

• Interleukin-2 (IL-2) is a critical cytokine for T cell activation, proliferation, and differentiation. During graft rejection, IL-2 promotes the clonal expansion of donor-specific T cells (both CD4+ and CD8+), which drive the immune attack on the transplanted tissue.

• IL-4 (b) is involved in B cell activation and Th2 responses (e.g., antibody production) but is not the primary T cell activator in rejection.

• IL-10 (c) is an anti-inflammatory cytokine that can suppress immune responses and may actually mitigate rejection.

• TNF-α (d) contributes to inflammation and graft damage but is not the key activator of T cells like IL-2.

• IgG antibodies are the primary mediators of antibody-mediated rejection (AMR) in transplantation. Preformed or donor-specific IgG antibodies (e.g., against HLA or ABO antigens) can bind to the graft endothelium, activate complement, and promote inflammation, leading to injury and rejection.

• IgG is highly effective at complement fixation and opsonization, making it a key player in hyperacute, acute, and chronic antibody-mediated rejection.

• Other options:

  • a) IgA: Involved in mucosal immunity but not typically in transplant rejection.

  • b) IgD: Functions as a B cell receptor; no major role in rejection.

  • c) IgE: Associated with allergic reactions and parasitic infections, not transplant rejection.

• Acute rejection (days to weeks post-transplant) is primarily mediated by recipient T cells recognizing donor HLA antigens.

• Therefore, HLA matching (especially HLA-A, HLA-B, and HLA-DR) significantly reduces the risk and severity of acute rejection.

Option breakdown:

• a) Hyperacute rejection → caused by preformed antibodies (e.g., ABO mismatch), not HLA mismatch.

• b) Correct → acute rejection is most reduced by HLA matching.

• c) Chronic rejection → multifactorial (immune + non-immune factors), HLA matching helps but is less effective.

• d) GVHD → mainly occurs in bone marrow transplants; HLA matching helps, but the question is about rejection of the graft.

• A positive crossmatch test indicates that the recipient has preformed antibodies (e.g., against donor HLA or ABO antigens) that could target the graft immediately after transplantation. This is a critical risk factor for hyperacute rejection, where the graft is rapidly destroyed within minutes to hours due to antibody-mediated complement activation and thrombosis.

• Crossmatch testing is routinely performed before transplantation to avoid this catastrophic outcome. If positive, it is typically a contraindication to proceeding with the transplant unless desensitization protocols are used.

Other options are incorrect:

• a): A perfect HLA match would likely result in a negative crossmatch, not positive.

• c): CMV exposure is assessed through serologic tests (e.g., IgG/IgM), not the crossmatch.

• d): A positive crossmatch predicts severe rejection, not acceptance; immunosuppression cannot prevent hyperacute rejection in this scenario.

• Even with HLA-identical siblings, differences in minor histocompatibility antigens (miHAs) can trigger graft-versus-host disease (GVHD). These are peptides derived from polymorphic cellular proteins presented by MHC molecules.

  • miHAs are not detected by standard HLA typing and can be encoded by genes on autosomes or sex chromosomes (e.g., HY antigens on the Y chromosome).

  • Donor T cells recognize these recipient-specific miHAs as foreign, leading to an immune attack on host tissues.

• Other options are incorrect:

  • a): While immunosuppression weakens the recipient’s ability to reject the graft, it is not the primary reason for GVHD.

  • c): ABO incompatibility is not always present and can be managed; it is not a primary cause of GVHD in HLA-identical transplants.

  • d): The number of mature T cells in the graft influences GVHD severity, but the fundamental cause is antigenic disparity (miHAs).

• In kidney transplantation, matching for HLA-A, HLA-B, and HLA-DR antigens is considered the most important for reducing the risk of rejection. These are the primary HLA molecules targeted by the recipient’s immune system.

  • HLA-A and HLA-B are Class I molecules expressed on almost all nucleated cells, including kidney cells, and are recognized by CD8+ T cells.

  • HLA-DR is a Class II molecule expressed on antigen-presenting cells and is recognized by CD4+ T cells, playing a key role in initiating immune responses.

• While other HLA molecules like HLA-C, HLA-DQ, and HLA-DP (b) can influence outcomes, they are less critical than HLA-A, HLA-B, and HLA-DR.

• The ABO system (c) is crucial for preventing hyperacute rejection but is separate from HLA matching.

• HLA-E and HLA-F (d) are non-classical HLA molecules with limited roles in immune regulation and are not prioritized in transplantation matching.

• Cyclosporine (also spelled ciclosporin) is a calcineurin inhibitor. It binds to cyclophilin (a cytoplasmic protein) and this complex inhibits the enzyme calcineurin. Calcineurin is critical for the dephosphorylation and activation of NFAT (Nuclear Factor of Activated T cells), a transcription factor that promotes the expression of interleukin-2 (IL-2) and other T cell activation genes. By inhibiting calcineurin, cyclosporine effectively suppresses T cell activation and proliferation, making it a cornerstone of immunosuppressive therapy in transplantation to prevent graft rejection.

• Methotrexate (b) is an antimetabolite that inhibits dihydrofolate reductase, interfering with DNA synthesis and used in autoimmune diseases and cancer, not primarily as a calcineurin inhibitor.

• Cortisone (c) is a corticosteroid that suppresses inflammation and immune responses broadly but does not specifically target calcineurin.

• Azathioprine (d) is a purine synthesis inhibitor that suppresses lymphocyte proliferation but is not a calcineurin inhibitor.

• Ankylosing spondylitis (AS) is a chronic inflammatory arthritis primarily affecting the spine and sacroiliac joints. It is strongly associated with the HLA-B27 genetic marker.

  • Over 90% of patients with AS test positive for HLA-B27, making it a key supportive diagnostic tool (though not definitive, as HLA-B27 can occur in healthy individuals and other diseases).

• CH50 levels (a and b) measure total complement activity. Decreased CH50 may occur in autoimmune conditions like lupus but is not specific to AS.

• Rheumatoid factor (d) is associated with rheumatoid arthritis, not AS. AS is seronegative (rheumatoid factor-negative).

• The mixed lymphocyte reaction (MLC or MLR) is an in vitro test that evaluates histocompatibility between a potential donor and recipient by measuring the proliferative response of T cells.

  • When lymphocytes from the donor and recipient are mixed, T cells from the recipient proliferate if they recognize foreign HLA class II antigens (e.g., HLA-DR, -DQ) on donor cells.

  • A strong proliferative response indicates significant HLA disparity and a higher risk of T-cell-mediated rejection.

• Other options are incorrect:

  • a) Antibody levels: Assessed through crossmatch or panel reactive antibody (PRA) tests, not MLC.

  • c) Complement activity: Measured via CH50 or AH50 assays.

  • d) ABO blood group compatibility: Determined through blood typing, not MLC.

• Chronic rejection develops over months to years and is characterized by progressive vascular damage (e.g., atherosclerosis of graft blood vessels), fibrosis (scarring), and gradual loss of graft function. It involves both antibody-mediated (humoral) and T cell–mediated immune responses, leading to chronic inflammation and tissue remodeling.

• Rapid necrosis of the graft (a) describes hyperacute rejection.

• Preformed antibody reaction (c) is key in hyperacute rejection.

• Chronic rejection does not involve an absence of inflammation (d); instead, it features chronic low-grade inflammation that drives fibrosis and vascular changes.

HLA (Human Leukocyte Antigen) matching between donor and recipient is critical in solid organ transplantation because it reduces the risk and severity of rejection episodes. A closer HLA match means the recipient’s immune system is less likely to recognize the donor organ as foreign, thereby decreasing the likelihood of both acute and chronic rejection. However, it does not eliminate the need for immunosuppression entirely.

The other options are incorrect because:

• a) HLA matching does not guarantee that the graft will never be rejected; other factors (e.g., non-HLA antigens, compliance with immunosuppression) also play roles.

• b) It does not eliminate the need for immunosuppressive drugs; even with a perfect HLA match, some immunosuppression is still required.

• d) It does not prevent viral infections; immunosuppressive drugs (necessary even with good matching) increase the risk of infections.

• An autograft is a graft where tissue is taken from one part of an individual’s body and transplanted to another site in the same individual. This avoids immune rejection since it is self-tissue.

• Allograft (a) is from a genetically different individual of the same species.

• Isograft (c) is from a genetically identical individual (e.g., an identical twin).

• Xenograft (d) is from a different species.

• Hyperacute rejection is triggered by pre-existing antibodies in the recipient (e.g., against ABO or HLA antigens on the donor graft). These antibodies bind to the graft endothelium and activate the classical complement pathway via C1q, leading to rapid complement cascade activation, inflammation, thrombosis, and graft destruction within minutes to hours.

• Other pathways:

  • b) Alternative pathway: Involved in innate immunity and amplification but not initiated by antibodies.

  • c) Lectin pathway: Activated by microbial carbohydrates, not antibodies.

  • d) Terminal pathway: Refers to the final steps (C5–C9) forming the membrane attack complex (MAC), but it is triggered by earlier pathways (classical, lectin, or alternative).

• Hyperacute rejection occurs within minutes to hours after transplantation. It is caused by pre-existing antibodies in the recipient that react against antigens on the donor graft (e.g., ABO blood group antigens or HLA antigens). This triggers rapid complement activation, thrombosis, and graft destruction.

• Acute rejection (a) typically occurs days to weeks post-transplant and is primarily T-cell-mediated.

• Chronic rejection (c) develops over months to years and involves both immune and non-immune factors leading to fibrosis and gradual loss of graft function.

The host-versus-graft (HVG) response describes the immune reaction where the recipient’s (host’s) immune system recognizes the transplanted organ (graft) as foreign and mounts an attack against it, leading to rejection. This is the primary barrier to successful transplantation and is the reason immunosuppressive therapy is necessary.

Why the other options are incorrect:

• a) This describes graft-versus-host disease (GVHD), which occurs primarily in bone marrow transplants where donor immune cells attack the recipient’s tissues.

• c) Mutual acceptance is the goal of immunosuppression and tolerance induction, not the HVG response.

• d) This refers to the process of histocompatibility testing (e.g., HLA matching), not the HVG response itself.

A major advantage of living donor kidney transplantation is that these grafts often have superior long-term outcomes compared to deceased donor grafts. This is due to several factors:

• Shorter cold ischemia time (the time the organ is without blood flow), which reduces injury to the organ.

• Better overall organ quality, as living donors are thoroughly evaluated and are generally healthy.

• The ability to schedule the transplant electively, optimizing the recipient’s condition.

The other options are incorrect because:

• a) HLA matching is still important for living donors to reduce rejection risk, though it may be more feasible to find a well-matched living donor.

• c) The surgical complexity for the recipient is similar regardless of the donor source.

• d) Graft-versus-host disease (GVHD) is extremely rare in solid organ transplantation (like kidney transplants) and is not a primary consideration; it does not eliminate the risk entirely.

• Hyperacute rejection occurs within minutes to hours after transplantation and is primarily mediated by pre-existing antibodies in the recipient against donor antigens (e.g., ABO blood group antigens or HLA antigens).

• IgM antibodies are the most responsible for this rapid rejection because:

  • They are potent activators of the complement system due to their pentameric structure, leading to immediate endothelial damage, thrombosis, and graft destruction.

  • Natural IgM antibodies against ABO antigens are particularly common triggers.

• While IgG antibodies can also contribute, IgM is often the initial and most effective mediator due to its strong complement-fixing ability.

• Other options are incorrect:

  • a) IgA: Involved in mucosal immunity; not a key player in hyperacute rejection.

  • c) IgE: Associated with allergic reactions and parasitic infections.

  • d) IgD: Functions mainly as a B-cell receptor; not involved in complement activation or rejection.