MICB 212 Chapter 16 Notes

Graft Rejection and Transplantation

-transplantation involves removal of organ, tissue or hematopoietic stem cells from a donor and placed into body of recipient

Autograft

• organ, tissue or hematopoietic stem cells is transplanted within same person’s body

• ex: veins from leg in a heart bypass surgery

Allograft

• organ, tissue or hematopoietic stem cells harvested from one individual and placed into body of a different individual

• alleles of MHC proteins on donor graft not normally present in recipient’s body (non-self-antigens)

• recipient may have T cells that bind strongly to these foreign MHC proteins on the transplanted person

• during negative selection process

  • T cells that bind to self MHC proteins too strongly are eliminated to avoid an immune response against own tissues

• possible that both T helper cells and naive CTLs have TCRs that bind to foreign MHC proteins on transplanted organ or tissue very strongly and induce an immune response against them → host vs graft disease

• if hematopoietic stem cells are transplanted into a recipient’s body with allograft → transplanted immune cells might recognize host’s MHC as foreign and mount an immune response against host’s cells, tissues, organs → graft vs host disease

-organs that have been successfully transplanted include

• heart

• kidney

• liver

• lungs

• pancrease

• intestine

• thymus

• uterus

-tissues that have been successfully transplanted are

• bones

• tendons

• corneae

• skin

• heart valves

• nerves

• veins

-different people have different versions of MHC proteins on their cells

• in transplantation → transplanted organs/tissues/hematopoietic cells from donor may have different proteins than those of recipient

Organ Rejection

Host vs Graft Disease

-occurs when recipient’s T cells mount an attack against the donor organ

-activation of T helper cells has consequences

• T helper cells infiltrate into graft → recruit and activate macrophages

• activated macrophages secrete proteases and other inflammatory mediators that damage the graft

• activated T helper cells also provide IL-2 that aids in activation of CTLs

-activated T helper cells also provide cytokine support to activated B cells that recognize foreign-MHC proteins

• these B cells differentiate into plasma cells that secrete antibodies that bind to foreign cells

• complement cascade is activated and membrane attack complex kills foreign cells

-CTLs that recognizes the foreign MHC class I proteins become activated CTLs and kills transplanted cells → graft rejection

-to improve chances of a successful transplant

• donors are HLA matched as closely as possible to recipient

-identical twin is the best donor since all their genes are identical

• grafts from identical twins are almost always accepted

• close relative is the next choice since they have an increased likelihood of shared MHC alleles

-if there are differences in MHC alleles between donated tissue and recipient

• necessary to prevent T cells from getting activated

• use drugs — Cyclosporin A — to suppress T cell function

  • increases risk of viral infections since ability to kill virus-infected cells is also suppressed

Indirect Allorecognition

• antigen presenting cells (APCs) from recipient take up and process MHC proteins from transplanted organ/tissue

• recipient T cells recognize the presented peptide as foreign and mount a response

Direct Allorecognition

• T cells become activated against graft through action of donor-derived antigen presenting cells

• transplanted into recipient with donated organ

• once in recipient’s body → donor-derived antigen presenting cells are able to move out of transplanted organ and interact with recipient’s T cells

• recipient T cells recognize MHC proteins on these donor derived APCs as foreign and react strongly

Summary

-successful organ transplantation is dependent on host’s immune system accepting the organ or tissue

-matching MHC proteins are important for minimizing rejection of foreign grafts in recipient

-besides matching MHC proteins, other ways to improve graft acceptance are

• drugs that suppress T cell function (cyclosporin A)

• healthier and less damaged organs

• better surgery techniques