MHCs and transplant immunology Flashcards by Yousof Tuffaha

How were MHC proteins discovered?

Antibodies against donor MHC proteins were discovered in patients who had received multiple blood transfusions and kidney transplant patients

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What is the alternative name for MHC proteins?

Human leukocyte antigen (HLA)

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What is the structure of a class II MHC protein?

A transmembrane α protein with two domains, non-covalently attached to
A transmembrane β protein with two domains

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What is the structure of a class I MHC protein?

A transmembrane α protein with three domains, non-covalently attached to
An extracellular β₂-microglobulin protein
The peptide-binding cleft is deeper than that of MHC-II proteins

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What are the strongest antigens produced on human cells?

HLAs

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How many alleles of MHC proteins does a human inherit?

6 for class I HLA (2 each of the three class I locus products)
6–8 for class II HLA

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What are the products of the class I MHC locus?

HLA-A
HLA-B
HLA-C

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What are the products of the class II MHC locus?

HLA-D

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What are the products of the “class III” MHC locus?

C2
C4
Factor B
TNF-α
TNF-β

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Which branch of the immune system (innate or adaptive) leads to transplant rejection?

Adaptive immunity

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Define

Autologous graft (autograft)

A graft transplanted from one individual to the same individual

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Define

Isograft (syngeneic graft)

A graft transplanted between two genetically identical individuals

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Define

Allogeneic graft (allograft)

A graft transplanted between two genetically different individuals of the same species

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Define

Xenogeneic graft (xenograft)

A graft transplanted between individuals of different species

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What is first-set rejection?

Rejection that occurs in a first-time allograft after recognition of the alloantigens by the adaptive immune system (similar to a primary immune response)

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What is second-set rejection?

Rejection that occurs in an allograft where the host is sensitized to the donor’s antigens (e.g. by inoculation with donor cells, previous transplantation) and shows features of a secondary immune response

Two mice, one with MHC^a and one with MHC^b, mate to give a child with hybrid MHC^a/b. What is the result of:
(a) transplantation of strain A mouse tissue into the hybrid?
(b) transplantation of strain B mouse tissue into the hybrid?

(a) No rejection, as the hybrid expresses MHC^a
(b) No rejection, as the hybrid expresses MHC^b

Two mice, one with MHC^a and one with MHC^b, mate to give a child with hybrid MHC^a/b. What is the result of:
(a) transplantation of the hybrid mouse’s tissue into a strain A mouse?
(b) transplantation of the hybrid mouse’s tissue into a strain B mouse?

(a) Rejection, as the hybrid contains MHC^b, while the strain A mouse does not
(b) Rejection, as the hybrid contains MHC^a, while the strain B mouse does not

What is direct recognition of alloantigens?

T cells recognize the donor’s MHC expressed in its native form on the graft cells

What is indirect recognition of alloantigens?

T cells recognize the donor’s MHC after processing by a host APC and binding on a self-MHC molecule

What is hyperacute rejection?

Rejection occurring within minutes to hours of the transplantation due to thrombotic occlusion of the graft’s vasculature

What is the pathophysiology of hyperacute rejection?

Preexisting antibodies in the host’s circulation bind to donor endothelial antigens on the endothelium, activating complement
Antibody and complement products induce changes in the graft’s endothelium leading to intravascular thrombosis and endothelium injury
The graft dies by ischemic necrosis due to severed blood supply

What is acute rejection?

Rejection (typically) occurring within days to weeks after alloreactive effector T cells and antibodies are produced

What is the pathophysiology of acute rejection?

Alloantigens are taken up by APCs, activating adaptive immunity in the usual fashion
CD8⁺ CTLs cause direct killing of the graft parenchyma
CD4⁺ T_H1 cells trigger cytokine release and inflammation
Alloantibodies (mainly against donor HLA) lead to endothelial injury and thrombosis (like in hyperacute rejection)

What is chronic rejection?

Gradual and insidious rejection taking place over months or years involving arterial occlusion in the graft

What is the pathophysiology of chronic rejection?

* Chronic inflammatory reactions occur in the intima of blood vessel walls, leading to proliferation of smooth muscles and vessel occlusion * In the kidney and heart, interstitial fibrosis occurs * In the lung, the airways thicken, leading to occlusion

What are the types of compatibility tests performed?

* ABO typing * Tissue typing * Crossmatching * Panel reactive antibody (PAR) test

What is the process of tissue typing in transplant compatibility?

A blood sample taken from the host is taken and tested for the types of HLA expressed. Samples from the donor tissue are taken and compared to identify the extent of allogeneity

What is the process of crossmatching in transplant compatibility?

* Cells from the donor are mixed with serum from the recipient * If host antibodies recognize the donor cells, complement-mediated cytotoxicity will occur, and the dead cells will be stained * If host antibodies do not recognize donor cells, no cytolysis will occur and the panel will not be stained

How can it be determined if a recipient is reacting to the donor's class I MHC or class II MHC?

Perform crossmatching on donor T cells and donor B cells (separately). Naive T cells express class I MHC, while Naive B cells express both classes. If the crossmatching result with T cells is negative, then the reaction is most likely against class II MHC

What are the phases of immunosuppressive therapy in transplantation patients?

* Induction phase at a high dose * Maintenance phase at a lower dose

What are examples of immunosuppressive drugs used in transplantation patients?

* Calcineurin inhibitors (e.g. cyclosporine, tacrolimus) * Steroids * Target of rapamycin (TOR) inhibitors * Azathioprine

What is graft-versus-host disease (GHVD)?

Rejection that occurs in hematopoietic stem cell transplants where the grafted donor cells react against body cells of the immunocompromised host

In what type of transplantation is GHVD prominent?

Transplantation of hematopoietic stem cells

Why can GHVD occur in people with identical HLA?

Normally, the reaction is directed against minor histocompatibility agents (miHAs), as HSC transplant is not performed when the donor and recepient have differences in MHC molecules

What is the pathophysiology of GHVD?

* Recipient conditioning: the host is immunocompromised by killing of the hematopoietic tissue before transplantation * Donor T cell activation: occurs in response to minor histocompatibility agents, leading to secretion of cytokines * Effector phase: T cells differentiate into their effector forms, leading to cytotoxicity, mostly in the liver, skin, and gut

# Define MHC restriction

A given T cell receptor is specific to a unique combination of both a peptide and a particular MHC molecule. T cells only recognize their antigens if they are presented on a native MHC protein