mhc and transplantation mhc & transplantation 周炫辰 邹知耕 张顺 郑艳 宗瑶 赵静
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MHC and transplantation
MHC &Transplantation
周炫辰 邹知耕 张顺郑艳 宗瑶 赵静
What is transplantation
TransplantationIn clinical practice,organ that has functional deficiency can be replaced by a normal organ from another person to make good a functional deficit,this therapy is called transplantation.
1909 - The first kidney transplant experiments were performed in humans in France using animal kidneys.
o A surgeon inserted slices of rabbit kidney into a child suffering from kidney failure. Although “the immediate results were excellent” the child died about 2 weeks later.
1954 - Joeseph E. Murray and his colleagues at Peter Bent Brigham Hospital in Boston performed the first truly successful kidney transplant between a pair of identical twins. This was done without any immunosuppressive medication.
More kidney transplants between identical twins were successfully performed, and some of those kidney recipients are still alive today
Graft
Donor
Recipient
Classification of transplantation
autograft: the same individual
isograft: genetically identical individuals, i.e., identical twins
allograft: the same species
xenograft: different species
(according to source of graft)
The greatest problem the transplantation is faced with is the rejection that ensues
After research,scientists have discovered that MHC play an important role in the rejection.
If the MHC is not identical between donor and recipient,it will cause immune rejection, leading to the death of the graft.
MHC——Major histocompatibility complex A large cluster of linked genes that encodes
two sets of highly polymorphic cell-surface
proteins,termed as:
class I MHC molecules→CD8+T cells
class II MHC molecules→CD4+T cells
MHC is also called HLA complex in human ,
but H-2 complex in the mouse.
Functions of MHC molecules
Present antigen to T cells and initiate immune respose.
T cell is activated only when MHC molecules bind to antigenic peptides.
• The structure of different MHC molecules are almost identical.
• The part of MHC molecule that is important in T cell recognition is the outer surface of the helices which is highly conserved.
• The significant differences between two MHC molecules lie deep in the peptide-binding groove between the helices ,governing which peptide can bind.
Molecular basis for interaction of MHC molecules and antigenic peptide
Mechanism of rejection
Graft and host MHC molecules present different peptides so that an immune response is triggerred.
Normal situation: MHC Peptide
T cell activationTransplantation: MHC
MHC
Peptide
Peptide
1.Direct recognition of alloantigens
Rejection
1.Direct recognition of alloantigens
The passenger leukocytes in the graft ,that is the DCs and macrophages ,also play an important role.
Quickly Strongly
2. Indirect recognition of alloantigens
Allotype MHC molecules can be as foreign protein processed by APC and recognized by T cell of recipient.
The recipient T cells recognize the peptide that is processed by recipient APC and is from donor MHC molecules.
Slowly Weakly
Role of CD4+ T cells and CD8+ T cells
CTL
MMHC II of self-APC
MHC II of graft-APCCD4+ T cell
MHC I of self-APCCD8+ T cell
(IL-2,IFN)
NK
B cell
MHC I of graft-cell
Graft-versus-host reaction GVHR
•A special situation occurs in bone-marrow transplantation ,in which GVHR is induced by immunologically competent T cells being transplantation into allogeneic recipients which are able to reject them.
Ways to prevent rejection
•Tissue typing (not completely)
•Immunosuppression (non-specific)
•Immunological tolerance (not practical)
Tissue typing by themixed lymphocyte reaction (MLR)
Immunosuppressive agents
application(s)mode of actionagent
corticosteroids, prednisone
anti-inflammatory, altering T-cell and PMN traffic
organ transplant, hypersensitivity, autoimmunity
cyclosporine, ticrolimus
inhibition of IL-2 production by T cells
organ transplant,
rapamycin Inhibition of T cell activation by IL-2
organ transplant
Immunosuppressive agentsImmunosuppressive agentsImmunosuppressive agents
application(s)mode of actionagent
azathioprine, 6-MP purine metabolism
organ transplant
methotrexate folate metabolism organ transplant
cyclophosphamide, melphalan
alkylation of DNA, RNA and proteins
autoimmune diseases, organ transplant
x-irradiation Lymphopenia malignancy/marrow transplantation
Alternative ways
•Stem cell
•Xenograft
The end
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