Lecture 27 - Transplantation

Transplantation = Act of transferring cells, tissues or organs from one site to another. ORGAN TRANSPLANTED Kidney Heart Lung Liver Cornea Pancreas, islets Bone marrow Small bowel Skin

DISEASE End-stage renal failure Terminal cardiac failure Pulmonary hypertension, CF Cirrhosis, cancer Dystrophy, keratitis Diabetes Immunodeficiency, leukemia Cancer Burns

Transplantation = Act of transferring cells, tissues or organs from one site to another.

Rejection = Damage done by immune system to transplanted organ or tissue.

Why are transplanted tissues rejected? Rejection of transplanted tissues occurs because immune system of the recipient recognizes and responds to foreign histocompatibility antigens expressed on the graft

Major inducers of allogeneic rejection reactions = = MHC or HLA antigens

Paternal = HLA-A1, B3, C5, DP3, DQ5, DR7 Maternal = HLA-A2, B4, C6, DP4, DQ6, DR8

A1

A2

DR7 DR8

B3 B4

C5 C6

DP3 DP4 DQ5 DQ6

Major inducers of allograft rejection = MHC or HLA antigens Weaker rejection = Minor H ags  weak 1st set reactions

First set reactions = “Primary” response Second set reactions = “Secondary” response

GRAFT

AUTOGRAFT ACCEPTANCE

1ST SET REJECTION

2nd SET REJECTION

2nd SET REJECTION

AUTOGRAFT ACCEPTANCE

1ST SET REJECTION

Allograft vascularized on day 5

Complete rejection on day 12

2nd set rejection on day 7

Foreign transplantation antigens

T cells activated

Cytokines produced

Effector mechanisms activated

Graft destruction

Graft rejection occurs in two stages:

1. The Sensitization stage 2. The Effector stage In the Sensitization stage, alloreactive lymphocytes proliferate in response to graft alloantigens; this involves CD4+ T cells and occurs in lymph nodes.

Sensitization Stage

Th

Th Th

Th

TDTH

TC TDTH

Graft rejection occurs in two stages: 1. The Sensitization stage 2. The Effector stage

In the Effector phase, stimulated host T cells and macrophages reach the graft; DTH and CTL reactions (and ADCC) and cytokines attack the graft.

1. T cells are central cells in rejection 2. Macrophages are also important (inflammation) 3. Antibodies are less important, but not unimportant

Th

Th Th

Th TDTH

TC TDTH Effector Stage

Sensitization Stage

Th

Th Th

Th TDTH

TC TDTH Effector Stage

Activated macrophage

Immunological Components of Graft Rejection

Acute Rejection: T cell-mediated, days/weeks

Chronic Rejection: Months/years

Hyperacute Rejection: Antibody-mediated

Graft versus Host Disease (GvHD) • Sort of a reverse of graft rejection • Graft attacks the host • When donor immunocompetent lymphoid cells attack immunocompromised host • Usually by T cell cytotoxicity • Diarrhea, skin lesions, jaundice, spleen enlargement, high mortality rate

Immunosuppression of Graft Rejection and GvHD To prevent the senitization of pre-existing mature T cells

General / Non-specific T cell inhibitors Cyclosporin Anti-inflammatory drugs Corticosteroids Inhibition of Mitosis Azathioprine Lymphoid irradiation

Specific

Corticosteroids inhibit presentation

Proliferation APC

Resting T

Activated T

T cell inhibitors inhibit activation Mitotic inhibitors inhibit proliferation

Immunosuppression of Graft Rejection and GvHD To prevent the senitization of pre-existing mature T cells

General / Non-specific T cell inhibitors Cyclosporin Anti-inflammatory drugs Corticosteroids Inhibition of Mitosis Azathioprine Lymphoid irradiation

Specific

Monoclonal antibodies to T cells

- Anti-CD3 antibodies - Anti-IL-2 Receptor abs - Anti-CD4 antibodies