Transplantation Immunology

Self-tolerance

prevents immune responses against self-antigen

Central Tolerance

deletion of self-reactive T and B cells during development

Peripheral Tolerance

control of escaped self-reactive cells (anergy, deletion, suppression)

Regulatory T cells (TREGs)

help maintain tolerance and limit immune responses

Activation of T cells:

requires costimulation (signal 1 + signal 2)

Absence of costimulation:

anergy (functional inactivation)

Breakdown of tolerance:

autoimmunity

Transplantation

Transferring:

• Cells

• Tissues

• Organs

Routine transplants include:

• Kidney

• Pancreas

• Heart

• Lung

• Liver

• Bone Marrow

• Cornea

Autograft

Self tissue

Isograft

Tissue from genetically identical individual (twin)

Allograft

Tissue from same species

Xenograft

Tissue from different species

Which transplant type would be expected to trigger the strongest immune response, assuming no immunosuppression?

Xenotransplantation

Blood group Ag differences:

• Most intense/fast graft rejections

• First items to be matched between donor/recipien

MHC compatibility is determined next:

• Siblings/parents are first choice

• Molecular assays provide a fast method of MHC screening to assess match quality

Agglutination Reactions

• Particulate antigen can interact to form cross-linking and visible clumping

• Antibodies capable of this are agglutinins

• Too much antibody causes a prozone effect

• Hemagglutination: agglutination of RBC

Antigenic Profiles: Typed for Histocompatibility

• The Major Histocompatibility Complex is the strongest force in rejection (MHC / HLA)

• Tissues that are antigenically similar are histocompatible

Dissimilar tissues are histoincompatible:

• MHC genes are most likely to lead to rejection

• Siblings have a 25% chance of MHC identity

• Parent-to-child grafts have a 50% MHC match (due to always having one MHC haplotype in common)

HLA compatibility testing combines three layers:

1. Genetic matching:

• Do donor and recipient share HLA alleles?

2. Antibody screening

• Does recipient already have anti-HLA antibodies?

3. Crossmatch test

• Do those antibodies facilitate attack against this specific donor?

Why are ABO blood group antigens matched before MHC typing?

ABO incompatibility causes immediate, life-threatening hyperacute rejection, whereas MHC mismatches generally lead to slower (acute or chronic) rejection

A patient has a good HLA genetic match but fails the crossmatch test. What does this imply?

The recipient has pre-existing antibodies that will likely attack the donor organ

Graph Rejection

Displays specificity and memory

Graft Rejection: Sensitization Stage

CD4+ and CD8+ T cells recognize alloantigens

• May be direct (recognize donor MHC)

• May be indirect (recognize peptides from donor MHCs presented on recipient’s own MHC)

• The T cells proliferate

• Memory T cells generated

Graft Rejection: Effector Stage

Variety of mechanisms:

• Heavy infiltration of recipient cells into graft tissus (similar to a DTH reaction)

• Can involve production of antibodies against donor HLA molecules or endothelial Ag

Hyperacute Graft Rejection

• Via pre-existing antibodies

• Occurs before grafted tissue ever revascularizes

• Antibodies bind to graft cells and activate complement

• Complete rejection may occur in as few as 24 hours

Steps of a Hyperacute Graft Rejection

1. Preexisting host antibodies are carried to kidney graft

2. Antibodies bind to antigens of renal capillaries and activate complement

3. Complement split products attract neutrophils, which release lytic enzymes

4. Neutrophil lytic enzymes destroy endothelial cells; platelets adhere to injured tissue, causing vascular blockage

Acute Graft Rejection

• Mediated by T-cell responses

• Responses begin 7–10 days post-transplantation

• Induce massive infiltration of lymphocytes and macrophages

• Suggests T_H -cell activation and proliferation

• Rejection occurs through mechanisms described for effector stage of graft rejection

Chronic Graft Rejection

• Develops months or years after acute rejection reactions have subsided

• Humoral and cell-mediated recipient responses:

  • Anti-rejection drugs help, but are not perfect

  • Work continues to make allograft transplants last longer or avoid rejection altogether

A graft is rejected within hours due to thrombosis and complement activation. What is the most likely cause?

Hyperacute Rejection

Avoiding Graft Rejection

• Anti-rejection drugs allow organ transplant between completely mismatched people

• Immunosuppressive therapy can be either general or target-specific

General Immunosuppressive Therapy

• Total lymphoid irradiation to eliminate lymphocytes

  • Often used in bone marrow transplants or to treat graft-versus-host disease (GvHD)

  • Effectively wipes out the recipient’s own immune cells, creating a situation where donor stem cells can engraft and form a “new” immune system

• Mitotic inhibitors (e.g., azathioprine) that diminishes B- and T-cell proliferation

• Fungal metabolites (e.g., cyclosporin A (CsA), rapamycin) that inhibit T_H -cell proliferation and cytokine expression

Specific Immunosuppressive Therapy

Ideal immunosuppressant is antigen-specific:

• Monoclonal antibodies:

  • mAb to CD3 (OKT3) depletes T cells prior to transplant

  • Soluble CTLA-4 fusion proteins (belatacept) can induce T-cell anergy

Why are general immunosuppressants (e.g., cyclosporin) problematic long-term?

They lack specificity—they suppress the entire immune system rather than just the targeted autoimmune or transplant-related response

• broad suppression, coupled with direct organ toxicity, leads to significant, often irreversible, damage over time

Why are antigen-specific therapies (e.g., CTLA-4 fusion proteins) preferred over general immunosuppressants?

they selectively target pathogenic (disease-causing) autoreactive immune cells while leaving the rest of the immune system functional

Allograft Tolerance: What types of tissues do we naturally tolerate?

Tissues that don’t have alloantigens:

• Cartilage, heart valves

Sequestered sites in the body:

• Absence of lymphatic vessels in tissue

• Cornea of the eye, brain, testes, and uterus

When there is early antigen exposure:

• Exposure during the organism’s development

T_REG Cells

• Presence and activities of T REG cells found in clinical operational tolerance cases

  • Situations where grafts are tolerated after complete removal of anti-rejection drugs

• Involvement of T REG cells and their cytokines in prevention of rejection is an area of active research