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