Lecture 28 - Transplantation

Types of transplantation

  • autograft: from self

    • because it is the patient’s own tissue, rejection risk is very low

  • allograft (allogenic): from a donor

    • this common type requires significant tissue matching to minimize rejection

  • xenograft: from a different species


Immune reactions preventing transplantation

  • blood typing

    • Blood types (A, B, AB, O) are determined by polysaccharide antigens on red blood cells

    • Individuals develop antibodies against antigens they lack (e.g., Type A has anti-B antibodies)

      • These antibodies arise due to exposure to similar antigens from gut microbiome bacteria

    • Type A: A antigen; anti-B antibodies

    • Type B: B antigen; anti-A antibodies

    • Type AB: A and B antigens; no anti-A or anti-B antibodies

    • Type O: Lacks A and B antigens; individuals have both anti-A and anti-B antibodies

    • The “O antigen” is not immunogenic, so no anti-O antibodies are produced

  • RBC antigens

    • “A” and “B” antigens are similar to antigens on common gut bacteria

    • unless negatively selected through self-tolerance, everyone has these pre-existing Ab to these antigens

    • similar to Type II hypersensitivity rxns (IgM/IgG-mediated)

  • blood transfusion reactions

    • incompatible transfusion (e.g., Type B blood into a Type A recipient) triggers the recipient’s pre-existing antibodies (anti-B) to attack donor red cells

      • this is a Type II hypersensitivity reaction: antibodies bind cells, activate complement, and cause cell destruction

    • RBC transfusions are relatively straightforward because RBCs do not express MHC molecules

  • Rhesus (rh) factor)

    • an Rh-negative mother carrying an Rh-positive fetus can be sensitized to Rh antigen at delivery when fetal blood mixes with maternal blood

    • after the first pregnancy, the mother develops anti-Rh antibodies; the first child is usually unaffected 

      • in subsequent Rh-positive pregnancies, maternal anti-Rh antibodies can cross the placenta and destroy fetal red cells, potentially fatal

    • prevention involves administering treatment that blocks maternal B-cell activation or antibody production against Rh (e.g., anti-D immunoglobulin)

Transplant rejection

  • certain sites (e.g., cornea) are “immune privileged,” with dampened immune responses

  • corneal transplants are less prone to rejection, contributing to their high success and frequency

  • host immune system recognizes transplant as non-self and attacks

    • solid organ transplant rejection

      • primarily driven by differences in MHC (HLA) between donor and recipient

        • donor–recipient HLA matching is crucial for transplant success

      • mixed lymphocyte reaction

        • the genetic loci responsible for whether this reaction occurs can be mapped using recombinant inbred mouse strains

        • the HLA locus is inherited as a block, making family members (parents, siblings) the most likely matches

        • many transplants proceed with partial (~50%) matches, requiring strong immunosuppression

    • MHC recognition also prevents cancer from being infectious

  • direct vs indirect allogentigen recognition of MHC

    • Direct recognition: donor dendritic cell, expresses its own MHC molecule, recipient T cell TCR binds strongly to “native” non-self MHC molecule

      • donor dendritic cells from the graft migrate to recipient lymph nodes and present donor self-antigens on donor MHC to recipient T cells, activating them; activated T cells then attack the graft

    • Indirect recognition: recipient dendritic cell, phagocytoses donor cell debris and presents (or cross-presents) peptides from donor MHC proteins on its own recipient MHC molecule, recipient T cell TCR binds strongly to peptides from non-self MHC molecule

      • recipient APCs infiltrate the graft, ingest donor cells, process donor antigens, and present donor-derived peptides on recipient MHC to recipient T cells, triggering an immune response

    • donor dendritic cells in transplanted organs migrate to lymph nodes and activated recipient T cells

      • recipient dendritic cells phagocytose donor cell debris, including MHC proteins

      • broken down in phagosome and loaded onto recipient MHC molecules

  • Type of transplant rejection:

    • hyperacute — due to pre-existing IgG Ab (previous blood transfusion)

      • occurs within hours

      • driven by pre-existing IgG antibodies from prior transfusions, pregnancies, or transplants, causing a rapid Type II hypersensitivity reaction

    • acute — due to adaptive responses from naiive cells activated for the first time (can be T or B cell-mediated)

      • occurs days to week

      • T-cell–mediated responses via direct and indirect pathways activate recipient CD4, CD8, and B cells to attack the graft

    • chronic — long-term secretion of cytokines stimulates proliferation of vascular smooth muscle cells; blood vessels become narrow & block blood flow

      • occurs months to years

      • persistent immune activation leads to inflammation, cytokine production, vascular intimal thickening, reduced perfusion, and eventual graft failure due to hypoxia

  • treatments to prevent transplant rejection

Graft-vs-host disease (GVHD)

  • hematopoietic cell transplants only, donor immune cells attack host tissue

    • donor immune cells transplanted with the graft (typically bone marrow) attack the recipient’s tissues

  • HSCT (bone marrow transplant) treats conditions like leukemia and multiple myeloma

  • potential problems: graft vs host disease & reduced immunity to microbes

  • hematopoietic cell transplantations contain:

    • hematopoietic stem cells (HSCs)

    • progenitors

    • lineage-committed cells

    • mature cells

  • mechanism of GVHD

    • patients are irradiated to ablate their hematopoietic stem cells, followed by infusion of donor marrow

    • donor graft contains mature T and B cells educated in the donor which are tolerant to donor tissues but recognize recipient tissues as foreign

      • donor T cells attack recipient cells and tissues, causing widespread damage

  • donor mature T cell can be activated against recipient antigens

    • went through (+) and (-) selection in the donor

    • not tolerant of “self” antigen in the recipient

  • reconstitutes stem cells and T cell progenitors that will continue development and maturation in the recipient

    • new T cell will undergo maturation in the recipients’ thymus, interacting with recipient epithelial cells for positive selection

    • positively selected to be able to bind to recipient MHC

      • donor-derived immature T cells mature in the recipient’s thymus and are selected on recipient MHC

  • many tissue-resident immune cells such as dendritic cells are from donor, expressing donor MHC

    • T cell positively selected against recipient MHC are not able to recognize antigen on donor MHC and are not able to be activated

    • during infection, recipient-trained T cells have difficulty recognizing antigens presented on donor MHC by donor APCs

      • this MHC mismatch between thymic training and peripheral presentation weakens immune responses, increasing infection susceptibility