Immunosuppressive Drugs and Transplantation

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Questions and Answers

What is the primary action mechanism of Azathioprine?

Stimulates B-cell differentiation

Inhibits nucleic acid synthesis (correct)

Inhibits calcineurin activity

Enhances T-cell proliferation

What is the principal limitation associated with the use of Azathioprine?

Toxicity to dividing cells (correct)

Nephrotoxicity

Increased cytokine production

Cardiotoxicity

Which drug is more potent than Cyclosporine in immunosuppression?

Methotrexate

Azathioprine

Tacrolimus (correct)

Glucocorticoids

What type of drug is Tacrolimus classified as?

Calcineurin inhibitor Signup and view all the answers

What is a common side effect of Tacrolimus?

Nephrotoxicity Signup and view all the answers

Which mechanism relates to the inhibition of T-cell cytokine production?

Blocking of calcineurin activity Signup and view all the answers

In what context is Tacrolimus commonly used?

Transplantation Signup and view all the answers

What is the relationship between HLA matching and the risk of rejection in transplantation?

A closer genetic match decreases risk of rejection. Signup and view all the answers

What adverse effect is associated with Azathioprine?

Increased risk of infections Signup and view all the answers

What can cause rejection even when there is a good HLA match?

Minor histocompatibility antigens Signup and view all the answers

Which class of HLA is primarily expressed on all nucleated cells?

Class I: HLA-A Signup and view all the answers

Which of the following statements about HLA inheritance is FALSE?

All individuals are HLA nonidentical. Signup and view all the answers

Which cells typically do NOT express HLA molecules?

T lymphocytes Signup and view all the answers

What is associated with rejection episodes and decreased graft survival?

MICA antibodies Signup and view all the answers

Which of the following blood group systems affects clinical transplantation?

ABO blood group antigens Signup and view all the answers

Which T cells receive presentations from Class II HLA molecules?

Helper T cells Signup and view all the answers

What is an autograft?

Tissue transfer from one area of the body to another of the same individual Signup and view all the answers

What is the primary mechanism of action for monoclonal antibodies in immunosuppressive therapy?

Inhibit T-cell activation or deplete lymphocytes Signup and view all the answers

Which type of graft is characterized by transferring tissue between genetically identical individuals?

Syngeneic graft (isograft) Signup and view all the answers

What potential side effect is associated with the use of polyclonal antibodies?

Severe rejection episodes Signup and view all the answers

What occurs during direct allorecognition?

Recipient T cells directly recognize intact foreign MHC molecules on donor cells Signup and view all the answers

Which pathway does not involve the direct recognition of donor MHC molecules?

Indirect allorecognition Signup and view all the answers

At what dosage condition is Sirolimus considered nephrotoxic?

High doses Signup and view all the answers

What can lead to graft rejection after a transplant?

Recognition of donor HLAs as foreign by the recipient's immune system Signup and view all the answers

What is a primary use of monoclonal antibodies in immunosuppressive therapy?

Induction therapy for severe rejection episodes Signup and view all the answers

One limitation of using polyclonal antibodies is the risk of what condition?

Serum sickness Signup and view all the answers

Which of the following describes an allograft?

Transfer of cells or tissue between genetically disparate individuals of the same species Signup and view all the answers

Which T-cell surface molecule is specifically targeted by some monoclonal antibodies?

CD25 Signup and view all the answers

What is primarily involved in the indirect allorecognition pathway?

Processing and presentation of foreign HLA proteins by antigen-presenting cells Signup and view all the answers

What type of graft involves transferring tissue between individuals of different species?

Xenograft Signup and view all the answers

What is a primary cause of preformed antibodies in a recipient's body?

Prior transplantation Signup and view all the answers

What is a significant risk when using humanized antibodies in immunosuppressive therapy?

Anti-mouse antibody response Signup and view all the answers

What is the primary mechanism by which hyperacute rejection occurs?

Immediate binding of preformed antibodies to donor antigens Signup and view all the answers

Which class of immunosuppressive drugs works by depleting circulating lymphocytes?

Polyclonal antibodies Signup and view all the answers

What preventive measure is important to reduce the risk of hyperacute rejection?

ABO compatibility matching Signup and view all the answers

In accelerated rejection, what primarily triggers the immune response in the recipient?

Re-exposure to donor tissue antigens Signup and view all the answers

What type of immune cells are predominantly involved in cellular alloresponse during acute rejection?

CD8+ T cells Signup and view all the answers

What occurs as a result of hyperacute rejection during transplantation?

It occurs within minutes to hours. Signup and view all the answers

What is a shared characteristic of both hyperacute and accelerated rejection?

Intravascular thrombosis and necrosis Signup and view all the answers

What is a typical timing for acute rejection to occur after transplantation?

Days to months after transplantation Signup and view all the answers

Which of the following is a correct remedy for hyperacute rejection?

Plasma exchange and intravenous immunoglobulin administration. Signup and view all the answers

What triggers the complement and clotting cascades in the context of antibody binding?

Antibody binding to antigens Signup and view all the answers

What must recipient–donor pairs be to avoid hyperacute rejection?

ABO identical or compatible. Signup and view all the answers

How do Killer Immunoglobulin-Like Receptors (KIRs) normally function?

They balance between activation and inhibition of NK cells. Signup and view all the answers

What happens when an NK cell encounters a cell with decreased HLA class I expression?

There is enhanced interaction with activating receptors. Signup and view all the answers

Why are stem cell donors selected based on the MHC protein type?

To promote alloreactivity by NK cells post-transplant. Signup and view all the answers

What is the outcome of alloreactive NK cells in transplant recipients?

They may prevent relapse in certain hematologic malignancies. Signup and view all the answers

Which option describes the consequence of engaging with inhibitory KIRs?

Inhibition of NK cell activation. Signup and view all the answers

Study Notes

Transplantation Immunology

Transplantation is the transfer of cells or tissues from one individual to another, or from one site to another within the same individual
It's a potentially life-saving treatment for end-stage organ failure, cancers, and autoimmune diseases
The genetic match between the donor and host is crucial for successful transplantation
A closer match means a lower risk of rejection
HLA typing is used to assess donor-recipient compatibility
The HLA system/MHC (major histocompatibility complex) is composed of Class I (HLA-A, HLA-B, HLA-C) and Class II (HLA-DR, HLA-DQ, HLA-DP) molecules
Class I molecules are expressed on all nucleated cells, presenting antigens to CD8+ T cells (cytotoxic T cells)
Class II molecules are expressed on antigen-presenting cells, presenting antigens to CD4+ T cells (helper T cells)
MHC genes are located on chromosome 6 , and exhibit substantial diversity (haplotypes)

Learning Objectives

Compare direct and indirect alloantigen recognition mechanisms
Distinguish between allograft, autograft, xenograft, and syngeneic graft (isograft) .
Compare immunologic mechanisms involved in hyperacute, acute, and chronic graft rejection
List the major classes of immunosuppressive agents and their effects on the immune system
Deduce the suitability of a potential donor for a transplant recipient based on HLA typing.

Transplant Types

Kidneys are the most common type of transplant for end-stage renal disease
Liver transplants are often performed for conditions like cirrhosis and hepatitis C
Heart transplants treat conditions such as cardiomyopathy and coronary artery disease
Lung transplants are used in cases of cystic fibrosis and emphysema
Pancreas transplants help patients with type 1 diabetes achieve insulin independence
Intestine transplants are used in cases of intestinal failure
Corneas are commonly transplanted due to their relative avascularity and low antigen concentration, resulting in a high success rate
Bone transplants, often using autografts or allografts, are used to repair bone fractures and correct abnormalities.
Intestinal transplants may be isolated (small intestine) or composite (with other organs). Recipients often have short gut syndrome.
Liver transplants are performed for conditions affecting the liver, with tacrolimus a common immunosuppressive treatment.
Lung transplants are the most challenging, with difficulties in bronchial matching, susceptibility to infections, rejection issues and high mortality.
Kidney transplants require strict recipient selection criteria to exclude patients with active sepsis, a history of malignancy or reactivating chronic infections. Careful matching of HLA-B and -DR loci is important for long-term survival .

Transplant Rejection

Hyperacute rejection occurs within minutes to hours post-transplant, mediated by preformed antibodies against donor antigens (e.g. ABO, HLA). Blood transfusions, previous transplants, or maternal exposure can lead to these preformed antibodies.
Acute rejection occurs days to months after transplantation, characterized by a cellular alloresonse (ACR) involving CD4+ and CD8+ T cells that directly damage the grafted tissue and an antibody-mediated response (AMR). Antibodies targeting vessels and resulting in inflammation can also damage the graft.
Chronic rejection occurs months or years after transplantation involving the delayed type hypersensitivity (DTH) response of the immune system targeting foreign HLA antigens in the graft. Cytokine release and macrophage activation contribute to smooth muscle accumulation leading to vascular damage, and graft loss.

Transplant Immunology

Graft-versus-host disease (GVHD): a reaction where donor T cells attack the recipient's tissues, typically arising after hematopoietic stem cell transplantation or lung/liver transplants
Acute GVHD: occurs within the first 100 days post-transplant, affecting the skin, gastrointestinal tract, and liver
Chronic GVHD): develops beyond 100 days post-transplant, affecting skin, eyes, mouth, and mucosal surfaces
Graft-versus-leukemia (GvL): a beneficial effect of donor immune cells (primarily T cells) in recognizing and eliminating residual leukemia cells in a transplant recipient, is often observed after a hematopoietic stem cell transplant and may reduce relapse risk.

Immunology Testing

HLA (Human Leukocyte Antigen) Typing: determines the genetic makeup of HLA antigens/genes and is crucial in donor-recipient testing. Antigens are tested, and phenotypes/genotypes of classical transplant antigens of genes (HLA A, B, Cw, DR, DQ) are measured to identify suitable pairs for transplant.
HLA Antibody Screening/Crossmatching: blood tests detecting antibodies that may activate rejection with an ELISA or flow cytometry method. Blood from the potential recipient and donor are tested for antibodies to donor HLA antigens.
Immunosuppressive drugs: used to minimize/treat rejection, including corticosteroids, cyclosporine, azathioprine tacrolimus, and sirolimus (rapamycin). Each has unique mechanisms of action and effects on the patient.

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Description

This quiz explores the mechanisms and limitations of immunosuppressive drugs such as Azathioprine and Tacrolimus. It delves into questions regarding T-cell cytokine production, HLA matching in transplantation, and the associated risks of rejection. Test your knowledge on these critical topics related to transplantation and immunology.