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Transplantation Immunobiology
2015.05.13 (수)
R3 이태규
Introduction
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The immune response to a transplanted graft can be
diveded into three phases :
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Recognition of foreign antigens
Activation of lymphocytes
Effector phase of graft rejection
Recognition of foreign antigens
MHC (Major Histocompatibility complex)
In human, HLA(Human Leukocyte antigen)
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m/i Genes that determine the rejection or acceptance.
on Chromosome 6
The greater differences in the MHC, the more rapid the
rejection.
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Encodes diverse cell surface proteins. (APC, Epithelial cell.. )
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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
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Highly polymorphic : e.g) HLA-A1, HLA-A2, .. > Polymorphism
Codominantly expressed : No recessiveness
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Present Ag to TCR(T-cell receptor) : T-cell activation
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Recognition of foreign antigens
Pathways of Alloantigen Presentation
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Activation of Recipient T-cell
Direct Antigen Presentation
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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
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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 Tcell(MHC Class I, Cellular immunity)
Chronic rejection에 책임이 있음
Recognition of foreign antigens
Minor Histocompatibility Antigens
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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 :
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anti-MICA Ab 가 형성될 경우 Graft survival에 좋지 않은 영
향을 미친다.
Recognition of foreign antigens
Site of T-cell – APC Interaction
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Vascular endothelium
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1st foreign Ag that recipient T-cell encounters.
MHC class I : Acute rejection > Vasculitis
Whole body
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Doner APC > Circulation > Whole body
Lymphoid tissue > Activates immune response > Rejection
Recognition of foreign antigens
Role of Graft Injury and Ischemia in the
Alloresponse
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Ischemia-Reperfusion Damage > Production of inflmmatory
cytokines > Recruitment of inflammatory cell > Activate
immune response.
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Acute rejection episodes are more frequent with grafts having
prolonged ischemia
Living, Unrelated donor > Deceased, Well-matched donor
Leukocyte Recruitment
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Endothelial cell activation > Selectin expression : “Rolling”
Chemokine secretion :
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Attract more leukocytes
Firm attachment of leukocyte to endothelium : Integrin (on leukocytes)
Extravasation
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E.g) LFA-1(Leukocyte factor antigen-1, Integrin의 일종) – ICAM1(Intercellular adhesion molecule-1)
LFA-1 or ICAM-1 Ab prolong graft survival in animals.
Activation of lymphocytes
T-Lymphocytes Activation
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TCR(T-Cell Receptor) : MHC molecule로부터 Ligand를 건네받아
Intracellular signaling을 개시.
CD3 complex :
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Important role in TCR Expression on cell surface and Intracellular signaling.
Muromonab OKT3 : CD3 inhibitor – One of the most potent
immunosuppressive agent.
Intracellular signaling
Activation of lymphocytes
T-Lymphocytes Activation
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CD4 and CD8 Subsets of T Cells
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Most mature T cells carry either the CD4 or CD8 protein on their
cell surface.
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CD4 : helper T-cell, binds to MHC class II.
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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.
Activation of lymphocytes
T-Lymphocytes Activation
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Type 1 and Type 2 Th-Cell Responses (Cytokine)
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Th1 cell : IL-2, IFN-r, IL-12, TNF
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Th2 cell : IL-4, IL-5, IL-10, IL-13
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DTH, Cytolytic activity, Opsonization, Complement-fixing IgG production
Acute rejection의 발생과 연관이 있는 작용.
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
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Strong inflammatory effect : Target of antirejection Tx?
Activation of lymphocytes
T-Lymphocytes Activation
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T-Cell Costimulation
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TCR – MHC 간의 작용 외 부가적으로 작용하여 T-cell activation
을 시키는 활동.
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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).)
Activation of lymphocytes
B-Lymphocytes Activation
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B-cell mediated(Ab) rejection : Hyperacute rejection(within
24hrs)
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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
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Foreign antigen recognition > Lymphocyte activation > 이
후 초래되는 부가 효과 및 결과.
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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