CBI Transplantation Immunology Lecture 2 PDF

Transplantation Immunology Lecture 2 Allograft Rejection of organ transplants Hershna Patel Acknowledgements: Dr Niall McMullen Aims and learning Outcomes Aims To promote awareness of: - how allograft rejection is initiated. - the processes of rejection. B...

Transplantation Immunology Lecture 2 Allograft Rejection of organ transplants Hershna Patel Acknowledgements: Dr Niall McMullen Aims and learning Outcomes Aims To promote awareness of: - how allograft rejection is initiated. - the processes of rejection. By the end of this session you should be able to: -describe the different stages of rejection -appreciate the role of DCs and HLA molecules in rejection. Organ transplant rejection - Introduction Differences in HLA haplotypes give rise to different HLA molecules between individuals. Donor HLA molecules alone may be seen as foreign. Donor HLA expressing peptide seen as foreign. Recipient HLA expressing donor-derived peptides. Organ transplant donor and recipient must be HLA-matched - tissue typing. Perfect matches rare – closer genetic relationship between donor and recipient reduces extent of polymorphic differences. Anti-rejection drugs used to control immune-mediated rejection.  Allograft rejection Immune response to alloantigens on donor (allo)graft. Displays specific (adaptive) immunological memory. Primarily involves recognition of donor MHC (HLA) molecules by alloreactive T cells (see direct and indirect presentation). High numbers of alloreactive T cells. Note: memory cells from previous infections cross-react with allogenic MHC molecules.  T cell recognition of alloantigens (1) Recognition of HLA alloantigens on ‘passenger’ leukocytes – typically DCs. (Myeloid DCs and plasmacytoid DCs) Donor DCs ‘trapped’ in graft. DCs express high numbers of both class I and class II HLA molecules. DCs also exhibit ‘cross -presentation’ – HLA class I molecules present peptides from the endocytic pathway. Alloantigen presentation  T cell recognition of alloantigens (2) 3 main methods: 1. Direct presentation – recipient T cells recognise intact HLA molecules alone and/or peptide:MHC complexes on donor cells. 2. Indirect presentation – recipient T cells recognise donor- derived peptides presented on recipient HLA molecules. 3. Semi-direct presentation (linked allorecognition) Involves direct transfer of HLA molecules between donor and patient DCs. Transfer may be facilitated by DC exosomes carrying donor MHC:peptide complexes. Exosomes released by T cell-activated DCs may participate directly in antigen presentation. Direct presentation of alloantigens: 2 models 1. Multiple binary determinant model: Individual alloreactive T cells recognise specific donor peptide presented on donor HLA molecule. Donor MHC molecules bind a wide range of peptides forming multiple peptide:MHC (pMHC) complexes….multiple individual T cell responses. 2. High determinant density model: Alloreactive T cells recognise donor HLA molecules directly (nonself!). Nature of peptide is irrelevant. High number of HLA molecules on donor cells results in multiple interactions. Boardman, et al,  Indirect presentation of alloantigens Patient DCs migrate into graft and acquire donor peptides (HLA). Patient DCs process donor HLA molecules. Alloreactive T cells recognise processed donor HLA molecules presented by patient DCs. May be most significant in chronic rejection – in cases of low numbers of donor DCs.  The immune response to alloantigens 1. Sensitisation phase: Donor DCs (passenger leukocytes) of donor migrate into lymph nodes of recipient. Alloreactive T cells primed and activated. Clonal expansion: Differentiation into effector cells – TH cells and CTLs. Alloreactive memory cells. Donor DCs initiate an inflammatory response- see following slide  Donor DCs in allograft rejection IL-1, IL-6, TNF-α, IL- 12 LaRosa, et al (2007). J Immunol ; 178 (12): 7503–  The immune response to alloantigens 2. Effector phase Driven by CD4+ TH cells. Cytokines increase immune activity and HLA expression (e.g. Il-2, IFN-γ). Activated endothelial cells expressing HLA are a major target. Cytokines increase expression of foreign HLA molecules CD8+ CTLs destroy donor cells expressing donor HLA class I molecules Antibody responses.  Patterns and mechanisms of organ rejection 1. Hyperacute rejection Very rapid occurs within hours of transplantation (very rare clinically). Due to pre-existing antibodies to donor antigens (HLA, blood group antigens)…second set rejection Destruction mediated via complement activation and ADCC  Vascular damage, thrombosis.  Patterns and mechanisms of organ rejection 2. Acute rejection Occurs in first few weeks post transplant. Primary response following sensitisation phase. Alloreactive CTLs destroy HLA class I-bearing donor cells. Antibody-mediated rejection of donor cells – endothelial cells primary target. Process amplified by alloreactive TH cells.  Patterns and mechanisms of organ rejection 3. Chronic rejection Occurs over years following transplant. Patient DCs mediate slow rejection process. Indirect presentation of alloantigens by recipient DCs. Slow build up of antibodies. Recurrence of disease. Which allograft is always tolerated?  Exercise A patient suffering from renal failure is awaiting a kidney transplant. Potential organs have become available. A limited microcytotoxicity typing test* was performed on four cadaver organs and the results are shown in the table below. The patient had been screened for serum antibodies and was positive for the antibodies used in wells 2 and 3 and negative for the antibodies used in wells 1 and 4. i. Which donor would be your first choice? ii. What is the immunological basis of your decision? iii. Why would the patient have anti-HLA antibodies? Summary Allograft rejection is an adaptive immune response. Process initiated by donor DCs and inflammatory environment. Different modes of alloantigen presentation/recognition. Direct recognition of donor MHC and/or donor peptide:MHC complexes. Indirect recognition of donor MHC-derived peptides presented by self-MHC on recipient APCs. Rejection involves a sensitisation and effector phase. Effector phase involves cell-mediated and antibody- mediated damage. Join menti.com  References/Recommended Reading Chapter 9 – Transfusion & Chapter 17 – Cellular & Chapter 15 – Janeway’s Transplantation Science. Molecular Immunology Immunology (615.39 TRA ) (616.079 ABB)