Transplantation immunology Dr Adel Almogren.

Transfusion vs. Transplantation  Transfusion  transfer of blood  Ab-mediated reactions  Transplantation  transfer of any other tissue/organ  T cell mediated reactions

Transplant Immunology Outline Introduction Graft compatibility Graft rejection Types of organ transplantation

Transplant Immunology Outline Introduction

Transplantationthe moving of cells, tissues, and organs from one site to another Graftthe transplanted organ Donorperson from whom graft is taken Recipient (host)person who gets the graft first transplant (living kidney) 1960s - liver, heart transplants

Surgical difficulties Graft rejection Organ shortage Introduction Transplantation problems

Transplant Immunology Outline Introduction Graft compatibility

Compatibility Rejection = recipient recognizes graft as foreign, and destroys it Autograftwithin same person Isograftbetween identical twins Allograftbetween genetically different people Xenograftbetween different species

Histocompatible: antigenically similar to the host Histoincompatible: antigenically different from the host MHC antigens are the most important ABO antigens are also important Minor histocompatiblity antigens are less important Compatibility Histocompatibility

Gene collection on chromosome 6 Three regions: class I, class II, class III Class I gene products HLA-A, HLA-B, HLA-C expressed on nearly all cells present antigen to T C cells Class II gene products DP, DQ, DR expressed on antigen-presenting cells present antigen to T H cells Compatibility HLA complex

Compatibility MHC class IIIIII Region ABCDPDQDRC4, C2, BF Gene products HLA- A HLA- B HLA- C DPDQDR C' proteins TNF-  TNF- 

HLA genes sit very close to each other Inherited as a set (“haplotype”) Everyone has two sets, one on each ch. 6 Genes are codominantly expressed (both maternal and paternal gene products are expressed in the same cell) Compatibility HLA inheritance

The more matching alleles between donor and host, the better! Matching the class II antigens is more important than matching the class I antigens. One or two class I mismatches = no big deal One or two class II mismatches = big deal Mismatches in both class I and II = very big deal Compatibility HLA inheritance

graft survival, % time after transplant, months 00 1 or 20 3 or or 2 3 or 41 or 2 number of mismatches Class I Class II

Transplant Immunology Outline Introduction Graft compatibility Graft rejection

1st set versus 2nd set reactions

Unprimed syngeneic recipient Role of cell mediated responses

Any two people (except identical twins) will express some HLA proteins that are different. Every recipient will recognize, and react against, at least some foreign antigens in the graft Rejection is complex, with lots of killing mechanisms. Rejection

Direct pathway of recognition Indirect pathway of recognition Rejection How do recipient cells know which cells to kill?

Direct PathwayIndirect Pathway

T-cell-mediated rejection Antibody-mediated rejection Rejection Two mechanisms of rejection

CD8+ CTLs kill graft cells directly CD4+ cells trigger a delayed hypersensitivity reaction Rejection T-cell mediated rejection

Role of CD4 + versus CD8 T + cells Injecting recip. mice with monoclonal Ab against CD8, CD4 or both to deplete one or both types of T cell

Hyperacute rejection Acute rejection Chronic rejection Rejection Clinical types of rejection

Clinical manifestations of graft rejection I.Hyperacute rejection: very quick II.Acute rejection: about 10 days (cell mediated) III.Chronic rejection: months-years (both)

Rejection Response

Transplant Immunology Outline Introduction Graft compatibility Graft rejection Types of organ transplantation

Most common transplanted organ Diabetes, glomerulonephritis, congenital disorders Problems: host sensitization post-transplant malignancy Types of Organ Transplantation Kidney

Cardiomyopathy, myocarditis, congenital defects, ischemic disease Must use heart-lung machine Problems: organ shortage maintaining graft before transplant atherosclerosis post-transplant lymphoma Heart Types of Organ Transplantation

Leukemia, lymphoma Find living donor (easy) that matches (hard) Massive chemo/radiation first Problem: GVHD Bone marrow Types of Organ Transplantation

Leukemia, lymphoma Find living donor (easy) that matches (hard) Massive chemo/radiation first Problem: GVHD Donor T cells see recipient as foreign! Attack skin, GI, liver Treat with immunosuppressives Or, partially deplete donor marrow of T cells Bone marrow Types of Organ Transplantation

Tissue Matching

General Immunosuppression Therapy

Problem 1 A 40 years old man who require a kidney graft due to end-stage renal disease. His HLA genotype was as follows: HLA-A3/A6.B27/B44,CI/C8,DR1/DR4. He brought 5 donors.and tissue typing was performed. Which one of them is the best choice ? Donor no.1 HLA type: HLA-A3/A8, B7/B28, C4/C8, DRI/DR4. Donor no.2 HLA “ : HLA-A6/A6, B27/B24, C12/C1, DR1/7. Donor no.3.HLA “ “ : HLA-A27/A44, B1/B8, C3/C6, DR3/DR14. Donor no.4 HLA “ ‘ : HLA-A3/A6, B24/B7,C2/C9, DR4/DR7. Donor no.5 HLA “ “ : HLA-A3/A3, B27/B44, C1/C8, DR4/DR4.

Problem 2 A 5-months old boy who was diagnosed with severe combined immunodeficiency (SCID ) received a bone marrow transplantation from an HLA-matched donor. He was doing well until 2 weeks after transplantation when he developed a skin rash. Subsequently he developed diarrhea, an enlarged liver & spleen and jaundice. What immunological process might be involved in his problem ?

Problem 3 A 45-year- old woman with end-stage renal disease due to diabetes mellitus, underwent renal transplantation. She received a kidney from a living, unrelated donor. Approximately one month after transplantation, the patient’s urine output and kidney function decreased. She developed tenderness, pain, and swelling at the graft site. In addition, she had nonspecific symptoms that included fever, decreased appetite, and myalgia (muscle pain).