Transplantation Immunobiology 2015.05.13 (수) R3 이태규

Introduction The immune response to a transplanted graft can be diveded into three phases : Recognition of foreign antigens Activation of lymphocytes Effector phase of graft rejection

MHC (Major Histocompatibility complex) Recognition of foreign antigens MHC (Major Histocompatibility complex) In human, HLA(Human Leukocyte antigen) m/i Genes that determine the rejection or acceptance. on Chromosome 6 The greater differences in the MHC, the more rapid the rejection. Encodes diverse cell surface proteins. (APC, Epithelial cell.. ) Class I : HLA-A, HLA-B, HLA-C > All nucleated cell (Epithelial cell) : Bind Intracellular peptide(Virus) Class II : HLA-DP, HLA-DQ, HLA-DR > APC(Dendritic cell, B-cell) : Bind Extracelluar peptide Highly polymorphic : e.g) HLA-A1, HLA-A2, .. > Polymorphism Codominantly expressed : No recessiveness Present Ag to TCR(T-cell receptor) : T-cell activation

Pathways of Alloantigen Presentation Recognition of foreign antigens Pathways of Alloantigen Presentation Activation of Recipient T-cell Direct Antigen Presentation 유입된 Donor APC가 발현하고 있는, 이질적인 MHC 그 자 체에 대하여(혹은 기타 Peptide와 함께) 반응 Acute rejection에 책임이 있음 : Direct:Indirect = 100:1 Indirect Antigen Presenation Recipient APC가, Donor의 이질적인 MHC를 삼키고, 이를 Ag로서 Recipient T-cell에 전달, 반응 : 원래 외부 물질에 대한 면역반응과 본질적으로 같음. CD4 T-cell(MHC Class II, Humoral immunity) > CD8 T- cell(MHC Class I, Cellular immunity) Chronic rejection에 책임이 있음

Minor Histocompatibility Antigens Recognition of foreign antigens Minor Histocompatibility Antigens Non-MHC molecules that can also mediate rejection. Even MHC matched siblings require immunosuppression therapy to prevent graft rejection. e.g) MICA(MHC class I-related chain A), MICB : anti-MICA Ab 가 형성될 경우 Graft survival에 좋지 않은 영 향을 미친다.

Site of T-cell – APC Interaction Recognition of foreign antigens Site of T-cell – APC Interaction Vascular endothelium 1st foreign Ag that recipient T-cell encounters. MHC class I : Acute rejection > Vasculitis Whole body Doner APC > Circulation > Whole body Lymphoid tissue > Activates immune response > Rejection

Role of Graft Injury and Ischemia in the Alloresponse Recognition of foreign antigens Role of Graft Injury and Ischemia in the Alloresponse Ischemia-Reperfusion Damage > Production of inflmmatory cytokines > Recruitment of inflammatory cell > Activate immune response. Acute rejection episodes are more frequent with grafts having prolonged ischemia Living, Unrelated donor > Deceased, Well-matched donor Leukocyte Recruitment Endothelial cell activation > Selectin expression : “Rolling” Chemokine secretion : Attract more leukocytes Firm attachment of leukocyte to endothelium : Integrin (on leukocytes) Extravasation E.g) LFA-1(Leukocyte factor antigen-1, Integrin의 일종) – ICAM- 1(Intercellular adhesion molecule-1) LFA-1 or ICAM-1 Ab prolong graft survival in animals.

T-Lymphocytes Activation Activation of lymphocytes T-Lymphocytes Activation TCR(T-Cell Receptor) : MHC molecule로부터 Ligand를 건네받아 Intracellular signaling을 개시. CD3 complex : Important role in TCR Expression on cell surface and Intracellular signaling. Muromonab OKT3 : CD3 inhibitor – One of the most potent immunosuppressive agent. Intracellular signaling

T-Lymphocytes Activation Activation of lymphocytes T-Lymphocytes Activation CD4 and CD8 Subsets of T Cells Most mature T cells carry either the CD4 or CD8 protein on their cell surface. CD4 : helper T-cell, binds to MHC class II. Initial recognition of allograft > amplify immune response > CD4 and CD8 effector cell ↑ (Delayed-type hypersensitivity) > Graft rejection CD8 : cytolytic T-cell, binds to MHC class I.

T-Lymphocytes Activation Activation of lymphocytes T-Lymphocytes Activation Type 1 and Type 2 Th-Cell Responses (Cytokine) Th1 cell : IL-2, IFN-r, IL-12, TNF DTH, Cytolytic activity, Opsonization, Complement-fixing IgG production Acute rejection의 발생과 연관이 있는 작용. Th2 cell : IL-4, IL-5, IL-10, IL-13 Eosinophil, IgE ↑ Th1을 억제함으로서 Graft tolerance와 연관이 있을 것으로 추정하나 불확실. 상호 억제 작용도 함께 수행하여 어느 한 쪽이 반응이 우세하 게 됨. Th17 cell : IL-17 Strong inflammatory effect : Target of antirejection Tx?

T-Lymphocytes Activation Activation of lymphocytes T-Lymphocytes Activation T-Cell Costimulation TCR – MHC 간의 작용 외 부가적으로 작용하여 T-cell activation 을 시키는 활동. T-cell – APC 간의 접착을 보다 공고히 하여 TCR의 Sampling time을 번 다. (LFA – ICAM) 다른 부가적인 신호를 통하여 T-cell mediated immune response를 조절 한다 (B7(APC ligand)/CD28(T-cell surface molecule) : T-cell proliferation 을 유발하나 Cytotoxic T-cell은 억제함(CTLA4).)

B-Lymphocytes Activation Activation of lymphocytes B-Lymphocytes Activation B-cell mediated(Ab) rejection : Hyperacute rejection(within 24hrs) 이전에 감작되어 ABO Ab, MHC Ab 등이 있을 경우. 또는 임신 의 기왕력. Memory B-cell activation에 걸리는 시간 및 Ab level이 낮을 경우 24시간을 초과하여 발생할 수 있음. T-cell mediated rejection과 함께 일어날 수 있음. (대개의 Rejection) Graft biopsy 상 C4d가 확인됨. Chronic rejection에도 관여하는 것으로 알려짐. CD20 : B-cell specific marker > Target agent를 통하여 B-cell mediated rejection의 치료를 노려볼 수 있음(Rituximab)

Effector phase of graft rejection Foreign antigen recognition > Lymphocyte activation > 이 후 초래되는 부가 효과 및 결과. Monocyte proliferation Proliferation and Activation of Cytolytic CD8 T cell, NK cell > Apoptosis 유발 B cell proliferation and differentiation to Plasma cell Plasma cell : Ig, Ab release > Ab dependent cellular toxicity(ADCC) Graft destruction