Chapter21 Transplantation

Immunology

History of transplantation 年代 学者 主要贡献1900 Landsteiner*(1930) 确定人红细胞主要的同种抗原　1912 Carrell* 器官移植　1948 Snell 和 Gorer 发现小鼠 H-2 系统及其与组织移植的关系1953 Snell*(1980) H-2 系统由 K 、 D 两个位点组成　1958 Dausset*(1980) 发现第一个人类白细胞抗原（ Mac ）　1962 Van Rood 鉴定出一个新的等位基因系统， 即 HLA-B 座位　1969 Amos 发现 HLA-D 座位1967 Benacerraf*(1980) 和 McDevitt 发现并证明 Ir 基因存在于 MHC 中　1970 Sandberg 鉴定出 HLA-C 座位1975 Doherty *(1996) 小鼠 H-2D 、 K 抗原对 Tc 杀伤病毒感染 细胞的限制作用1978 Rosenthal Ir 基因产物 Ia 抗原参与 Mφ-T 相互作用1978 Zinkernagel * (1996) MHC 对 T 细胞发育分化的影响1987 Tonegawa* 　 Ig 的基因结构1990 Murray 和 Thomas* 肾移植和骨髓移植　　* 诺贝尔奖获得者，括号内为获奖年代

PartⅠ Introduction PartⅡ Immunologic mechanism of allogeneic transplantation rejectionPartⅢ Classification and effector mechanisms of allograft rejectionPartⅣ Prevention and treatment of allograft rejectionPartⅤ Exnogtransplantaion

contentscontents

PartⅠ Introduction

• Transplantation: the process of taking cells, tissues, or organs from one individual and placing them into a different individual or different site of the same individual.

• Graft: transplanted cells, tissues, or organs.

• Donor: the individual who provides the graft.

• Recipient: the individual who receives the

graft. Also called the host.

• Autologous graft (Autograft): • Syngeneic graft (Isograft ): • Allogeneic graft (Allograft): • Xenogeneic graft (Xenograft ):

autologous transplantation

isogeneic transplantation

heterogous transplantation

• Autograft

• Isograft

• Allograft

• Xenograft

• The most formidable barrier is the immune system.

• Allograft Rejection Displays Specificity and Memory.

lymphocytes

(strain C)

PartⅡ Immunologic mechanism of allogeneic

transplantation rejection

• Transplantation antigens

• Mechanism of allograft rejection

1. Transplantation antigens

• Major histocompatibility antigens (MHC molecules)

• Minor histocompatibility antigens

• ABO Blood group antigens and tissue specific antigens

2. Mechanism of allograft rejection

The immune responses in allogeneic transplantation:

T cell mediated rejection of allograftAntibody mediated rejection of allograft NK cell mediated rejection of allograft

• T Cells Play a Key Role in Allograft Rejection

10 days 3 days

3 days

(1) T cell mediated rejection of allograft

(mechanism of cellular immunity)

1) Recognition of alloantigens

2)Activation of T cells and rejection of allograft

1) Recognition of alloantigens

• Direct recognition ------acute rejection

• Indirect recognition ------chronic rejection

① Direct recognition of alloantigens

• Recognition of an intact MHC molecule displayed by donor APC in the graft.

• An allogeneic MHC molecule with a bound peptide can mimic the determinant formed by a self MHC molecule plus peptide.

• Passenger leukocytes

The donor APCs that exist in grafts.

Fast and strong reaction in acute rejection

• Direct recognition is a cross-reaction of a normal TCR, which was selected to recognize a self MHC molecules plus foreign peptide, with an allogeneic MHC molecule (plus peptide).

• As many as 2% of an individual’s T cells are capable of directly recognizing and responding to a single foreign MHC molecule.

Direct recognition of TCR to allogeneic MHC molecules

CD8+T

CD8+T

CD4+T

T cell from recipient

APC from donor

CTL

CTL T cells from host

donor tissue cells

Direct recognition of TCR to allogeneic MHC molecules

② indirect recognition of alloantigens

• the donor MHC molecules may be processed and presented by recipient APCs that enter grafts, and the processed MHC molecules are recognized by T cells like conventional foreign antigens.

Host APC

Graft are uptaked by self APC

processing

Presentation by self APC

CD8+T

CD4+T

CD8+T

Host T cell

Indirect recognition of TCR to allogeneic MHC molecules

2) Activation of T cells and rejection of allograft

Host T cells may be activated by both direct recognition and indirect recognition

• Direct pathway : CD4+T ---- Th CD8+T ---- CTL ---- killing graft cells

• Indirect pathway : CD4+T ---- infiltrate the graft and recognize donor

alloantigens being displayed by host APCs that have entered the graft ---- Th

CD8+T ---- can not directly kill the foreign cells in the graft

• T Cells Play a Key Role in Allograft Rejection

Direct allorecognition

Indirect allorecognition

MHC Intact allogeneic MHC

Antigenic peptide of allogeneic MHC

APC Recipient APC not necessary

APC of recipient

Activated T cell CD4+T or CD8+ T CD4+T (or CD8+ T)

Functions in graft rejection

Acute graft rejection Chronic graft rejection

Degree of rejection Very strong weak

Difference between direct and indirect allorecognition

(2) Antibody-mediated rejection of allograft (mechanism of humoral immunity)Ⅰ ． Complement activated by antibody involved in transplantation rejection

Ⅱ.Antibody participate in transplantation rejection through ADCC and opsonization

III. Enhancing antibody and transplantation rejection enhancing antibody+transplantation antigen →block other antibodies or T cells binding to antigen. Also called blocking antibody

(3) NK cell mediated rejection of allograft

• KIR can’t recognize allogeneic MHC of graft

• CKs secreted by activated Th cells can promote NK activation.

PartⅢ Classification and effector mechanisms of

allograft rejection

• Host versus graft reaction (HVGR)

① Hyperacute

② Acute

③ Chronic

• Graft versus host reaction (GVHR)

① Hyperacute rejection: • It begins within minutes to 1-2days after host blood

vessels are anastomosed to graft vessels.• It is characterized by thrombotic occlusion of the

graft vasculature.• It is mediated by preexisting antibodies in the host

circulation that bind to donor endothelial antigens.• ------ Complement activation, endothelial damage,

inflammation, thrombosis.• Immune suppression is not effective

Host versus graft reaction (HVGR)

Host versus graft reaction (HVGR)

Acute tubulointerstitial rejection: Mononuclear interstitial infiltrate.

③ Chronic rejection :• It develops months or years after acute rejection reactions

have subsided. • It is characterized by fibrosis and vascular abnormalities

with loss of graft function.• The mechanisms of chronic rejection include both

humoral and cell-mediated responses .• -------chronic DTH reaction in vessel wall, intimal smooth

muscle cell proliferation, vessel occlusion.

Host versus graft reaction (HVGR)

Chronic Vascular Rejection - Concentric Fibrous Intimal Thickening and Lymphocytic Infiltration

Graft versus host reaction (GVHR)

Graft versus host diseas (GVHD)

BM transplantation

GVHD: a disease occuring in bone marrow transplant recipients that is caused by the reaction of mature T cells in the marrow graft with alloantigens on host cells. The diease most often affects the skin, liver, and intestines.

PartⅣ Prevention and treatment of allograft

rejection

① Reducing the immunogenicity of allografts （ tissue typing)

② Immunosuppression

③ Inducing donor-specific tolerance

① Reducing the Immunogenicity of allografts:

• Donors and Recipients Are Typed for RBC and MHC Antigens

Blood group antigens matching

MHC matching

• HLA-A, B and HLA-DR is important for predicting outcome.

Mixed lymphocyte reaction to determine identity of class II HLA antigens between a potential donor and recipient. Lymphocytes from the donor are irradiated or treated with mitomycin C . If the class II antigens on the two cell populations are different, the recipient cells will divide rapidly and take up large quantities of radioactive nucleotides into the newly synthesized nuclear DNA. The amount of radioactive nucleotide uptake is roughly proportionate to the MHC class II differences between the donor and recipient lymphocytes.

② Immunosuppression:

• Immunosuppressive drugs that inhibit or kill T cells are the principal treatment regimen for graft rejection.

Cyclosporine(CsA), FK506 • Antibodies that react with T cell surface structures

and deplete or inhibit T cells are used to treat acute rejection episodes.

• Anti-inflammatory agents are also routinely used. – Corticosteroids to block the synthesis and secretion of

cytokines.

③ Inducing donor-specific tolerance:

• Blocking T cell activation

• Th2 cytokines

• microchimerism

PartⅤ Exnogtransplantaion

• lack of organs for transplantation.

The seriousness of the donor organ shortage is reflected in the fact that, as of November 2000, an estimated 73,000 patients in the United States were on the waiting list for an organ transplantation. The majority of those on the list (~70%) require a kidney; at present, the waiting period for this organ averages over 800 days.

Summary

• Direct recognition, Indirect recognition

• Immunologic mechanism of allogeneic transplantation reject

• Classification and effector mechanisms of allograft rejection

• Prevention and treatment of allograft rejection