What is transplant rejection?
Destruction of grafted tissue by the acquired immune system of the recipient host. The immune response that destroys grafted tissue is directed at unique determinants that arise due to genetic differences b/t donor and recipient.
What does allogeneic mean?
Describes individuals of the same species that are genetically different - these differences are caused by genetic polymorphisms
What are the most polymorphic genes in the human genome?
MHC I and MHC II
In addition to MHC, name some additional polymorphic genes in our genome.
- Blood group antigens: have a huge impact on successful engraftment of tissues between different people
- Minor histocompatibility antigens
What is an autograft?
- A graft of tissue from one part of the body to another
- Genetically identical to the recipient b/c recipient is also donor (so it should not be rejected)
- Aka, isograft
What is a syngeneic graft?
One in which the donor and the recipient are genetically identical (i.e., identical twins) -> no rejection should be expected
What is an allograft?
- A graft b/t two patients that are not genetically identical
- Graft will be rejected unless appropriate immunosuppressive drugs are used appropriately in the recipient
What is a zenograft?
A graft b/t two different species (will certainly be an allograft as well)
How are allogeneic solid tissue grafts destroyed (rejected) by the host?
Primarily by T cells that have specificity for alloantigens on the grafted tissue
What are the most common tissue grafts?
Blood transfusions: it is critical that proper tissue cross-matching be performed prior to blood transfusion b/c alloreactions can be fatal
What are the primary targets of alloreactions following a blood transfusion?
- A and B blood group antigens are the primary targets of alloreactivity in this case
- These alloreactions do NOT involve T cells because RBCs do not produce MHC I or II
Which blood type is a universal donor? Why?
- O type can be safely transfused into patients that have any blood type because NO ONE should have Abs specific for O antigen in their blood
- O blood group antigen is the core structure for the A and B group antigens
Which blood type is a universal recipient? Why?
Type AB blood people are universal recipients b/c they do not have any anti-A or anti-B Abs in their circulation
What are Rh factors?
- A group of proteins (alloantigens) expressed on RBCs that must be considered prior to transfusion
- Over 50, but RhD most important
What is the difference b/t Rh factors and blood type antigens?
- There are no normal flora pathogens that produce structures similar to Rh factors, so a person who has never had a transfusion should not have ever mounted an Ab response to any of the Rh factors
- RhD is considered before giving a transplant to ensure patients will not be exposed to Rh factors they do not express
What is hyperacute rejection?
- Easily prevented, but mistakes can happen
- Mediated by preformed Abs specific for alloantigens expressed on grafted tissue
- Most common cause is transplantation from donor whose blood type is not compatible with recipients
Describe the immune response in hyperacute rejection of tissue.
- Vascular endo expresses same blood group antigens found on RBCs, so anti-A or anti-B antibodies will bind A or B antigens on vascular endo, initiating complement cascade and promoting phagocyte influx into tissues
- As phagocytes recognize Fc regions of Abs and complement opsonins via Fc and complement receptors, they produce inflammatory mediators
- Platelets will bind activated endo, resulting in occlusion of small vessels -> inflammatory response kills grafted tissue w/in 48 hours in most cases
What is acute transplant rejection?
- Typically mediated by CTLs that have specificity for alloantigens on grafted tissue (almost always products of polymorphic genes, esp. MHC I and II)
- Recipient should have no preformed immune response to any alloantigens on donated tissue, so recipient has to prime response after graft is introduced into recipient's body
- Typically takes 11-15 days for tissue to be rejected post-transplantation, assuming no anti-inflammatory drug treatment is being administered (which it always will be in future cases, unless otherwise noted)
What is the primary immune response responsible for killing donor tissue in recipient in acute transplant rejection?
- CD8 effector cells
- Mouse model example from lecture:
1. When only CD8's were harvested from mouse that had already generated response to grafted tissue, and put into previously unaffected mouse receiving graft, rejection occurred more rapidly -> 4-7 days
2. First-set vs. second-set rejection: second-set reaction may be so fast (e.g., skin graft example) that grafted tissue never even becomes vascularized
What are the 2 mechanisms for priming of acute graft rejection?
1. APCs from donor tissue migrate to secondary lymphoid tissue of recipient. Because they express same alloAg's (MHC I-derived peptides, chiefly), these allogeneic peptides will be presented to naive host T cells, priming CTL response to donated tissue
2. Recipient APCs will also take up pieces of grafted cells that have died and present determinants of donor tissue to naive T cells in secondary lymphoid tissues
How is MHC haplotype matching performed?
- Based on a combo of serological studies and DNA-based techniques to determine degree of match between recipient and potential donors
1. This matching can vastly improve chances of transplantation success
- Degree of matching at HLA-A, HLA-B, and HLA-DR loci appear to be most important for successful transplant (for unknown reasons)
REMEMBER: anti-inflammatory drug regimens very important to success of transplantation of any tissue that has allogeneic determinants
Is it possible for grafted tissue between donor and recipient that have identical MHC haplotype to be rejected?
- Yes - because there are other polymorphic genes, e.g., minor histocompatibility antigens
1. Several of these are also encoded in MHC locus of genes
- Rejection due to responses directed only against minor HCs take significantly longer than typical acute rejection (30-60 days)