Transplantation Immunology Lecture 2

Transplantation Immunology Lecture 2: Allograft Rejection

• Allograft rejection is an immune response to foreign tissues.
• HLA (Human Leukocyte Antigen) molecules differ between individuals.
• Donor HLA molecules can be recognized as foreign by the recipient.
• Recipient HLA molecules can also recognize donor peptides as foreign.
• Organ transplant recipients and donors need to be HLA-matched to decrease rejection risk.
• Perfect HLA matches are rare and associated with close genetic relationships between donor and recipient.
• Immune response to alloantigens on the donor graft displays adaptive immunological memory.
• Allograft rejection primarily involves alloreactive T cells recognizing donor MHC (HLA) molecules.
• These T cells have high numbers and arise from previous infections crossing over to the MHC.

Aims and Learning Outcomes

• The aim of the lecture is to raise awareness of allograft rejection initiation and the rejection process.
• By the end of this session students should be able to describe the rejection stages and understand the role of dendritic cells (DCs) and HLA molecules in rejection.

Organ Transplant Rejection - Introduction

• Variations in HLA haplotypes lead to different HLA molecules among individuals.
• Donor HLA molecules can be perceived as foreign.
• Recipient HLA molecules recognize donor-derived peptides.
• HLA matching between donor and recipient is essential for successful tissue typing.
• Matching is crucial to reduce rejection arising from polymorphic differences.
• Anti-rejection drugs are used to manage immune-mediated rejection.

Allograft Rejection

• The immune system responds to alloantigens on the donor graft/organ.
• Allograft rejection demonstrates adaptive immunological memory.
• The primary mechanism involves allo-reactive T cells (TCR) recognizing donor MHC (HLA) molecules via direct or indirect presentation methods.
• High numbers of alloreactive T cells contribute significantly to the rejection process.
• Memory cells from past infections may cross-react with allogeneic MHC molecules in the implanted tissues, stimulating rejection.

T Cell Recognition of Alloantigens (1)

• T cells recognize alloantigens on passenger leukocytes, typically dendritic cells (DCs).
• Two types of DCs, myeloid DCs and plasmacytoid DCs, are involved.
• Donor DCs are often "trapped" within the transplanted graft.
• DCs express a high number of both class I and class II HLA molecules.
• DCs employ cross-presentation, where HLA class I molecules use the endocytic pathway to present peptides.

Alloantigen Presentation

• Direct, Indirect, and Linked allorecognition are different pathways for alloantigen recognition.
• Visual diagrams illustrate these recognition pathways.

T Cell Recognition of Alloantigens (2)

• Three main methods for T cell recognition exist:
  • Direct presentation - recipient T cells recognize intact donor HLA molecules.
  • Indirect presentation - recipient T cells recognize donor-derived peptides presented by recipient HLA molecules.
  • Semi-direct presentation (linked allorecognition) - involves direct transfer of HLA molecules between donor and recipient DCs.

Direct Presentation of Alloantigens: 2 Models

• Multiple binary determinant model - individual alloreactive T cells recognize specific donor peptides presented on donor HLA molecules. Donor MHC molecules bind various peptides, causing multiple T cell responses.
• High determinant density model - alloreactive T cells directly recognize donor HLA molecules. Peptide nature is irrelevant. Many HLA molecules on donor cells lead to more T cell interactions.

Indirect Presentation of Alloantigens

• Patient DCs migrate into the graft and acquire donor peptides (HLA).
• Within the graft, patient DCs process and present donor HLA molecules.
• This presentation triggers alloreactive T cells to recognize and target the donor HLA molecules.
• Chronic rejection may partially depend on the number of donor DCs present.

The Immune Response to Alloantigens: Sensitization Phase

• Donor DCs (passenger leukocytes) migrate to recipient lymph nodes.
• Alloreactive T cells are primed and activated.
• T cells proliferate, differentiating into effector cells (TH, CTLs) and alloreactive memory cells.
• Donor DCs initiate an inflammatory response.

Donor DCs in Allograft Rejection

• Donor DCs are important in allograft rejection.
• Visual diagram shows their role in different stages of rejection, including procuring donor organs and initiating inflammation.
• Immune factors and cell types in the graft are illustrated.

The Immune Response to Alloantigens: Effector Phase

• The effector phase is driven by CD4+ T cells.
• Cytokines increase immune responses and HLA expression (e.g., IL-2, IFN-γ).
• Activated endothelial cells expressing HLA are major targets.
• These cells increase foreign HLA molecule expression due to cytokines.
• CD8+ cytotoxic T lymphocytes (CTLs) destroy donor cells expressing donor HLA class I molecules.
• Antibody responses also participate in this phase.

Patterns and Mechanisms of Organ Rejection: Hyperacute Rejection

• Occurs within hours of transplantation.
• Pre-existing antibodies in the recipient target donor antigens (HLA, blood group).
• Complement activation and antibody-dependent cellular cytotoxicity (ADCC) cause endothelial damage and thrombosis.

Patterns and Mechanisms of Organ Rejection: Acute Rejection

• Occurs within the first few weeks.
• A primary immune response ensues during the sensitization phase.
• Alloreactive CTLs target HLA class I-bearing donor cells.
• Antibody-mediated rejection primarily targets endothelial cells.
• This process is amplified by alloreactive T helper cells.

Patterns and Mechanisms of Organ Rejection: Chronic Rejection

• Occurs over years.
• Recipient DCs mediate the slow rejection process.
• Alloantigens are presented indirectly by recipient DCs.
• A slow build-up of antibodies may correlate with chronic rejection.
• Disease recurrence is a potential outcome.

Which allograft is always tolerated?

• This question is designed to provoke thought. Self-grafts are typically tolerated.

Exercise (Case Study)

• The provided table lists microcytotoxicity typing results for potential kidney donors.
• The patient has antibodies to specific HLA types.
• The exercise asks to select the appropriate donor.
• The basis for choosing the donor should be explained in terms of immunology.
• Reasons for the patient's anti-HLA antibodies should also be considered.

Summary

• Allograft rejection is an adaptive immune response triggered by donor DCs and inflammatory processes.
• The process involves different methods of alloantigen presentation and recognition.
• Rejection includes sensitization and effector phases with cell-mediated and antibody-mediated damage.

This lecture covers the critical processes involved in allograft rejection, focusing on the role of HLA molecules and the immune response. Learn about the importance of HLA matching between donors and recipients, as well as the adaptive memory of alloreactive T cells. Enhance your understanding of how rejection mechanisms operate in organ transplantation.