(1) ABO blood groups on RBCs – transplant and donor must match on these.
(2) HLA – Human Leukocyte Antigen (same as MHC).
Þ HLA-A, HLA-B, HLA-C
MHC class II Þ HLA-DR, HLA-DQ, HLA-DP
- Human MHC molecules are coded by the following genes:
Major vs. Minor Histocompatibility Loci and Antigens
All H antigens encoded at MHC loci are termed Major H antigens; All H antigens encoded at non-MHC loci are termed minor H antigens
A difference between the donor’s and recipient’s major H loci will result in a quick graft rejection. (i.e. a difference in MHC class I and II).
A difference between the donor’s and recipient’s minor H loci will result in a slower graft rejection, and will thus require a smaller amount of immunosuppression.
What is a Minor H antigen? (another explanation) – If a recipient was so lucky as to get a graft that has identical MHC-I and MHC-II to his/her own, the graft would still be rejected in the long term. The reason for this is that the donor’s MHC molecules will present ‘self’ peptides (i.e. peptides from the graft) that the recipient’s T cells were not educated to recognize as ‘self’. As such the recipient’s T cells will attack the graft regardless of the identical MHCs.
Among siblings in a single family, there is a 25% chance for both haplotypes to be shared, a 50% chance for one haplotype to be shared, and a 25% chance for no haplotypes to be shared. For example, if the father is haplotype AB, the mother is CD, and the recipient child is AC, there is a 25% chance for a sibling to be AC, i.e., a two-haplotype match, a 50% chance for a sibling to be either BC or AD, i.e., a one-haplotype match, and a 25% chance for a sibling to be BD, i.e., a zero-haplotype match.
- it is possible to make antibodies to major H antigens but not minor H antigens
Autograft – transfer of an individual’s own tissue
Isograft (syngraft) – transfer of tissue between genetically identical individuals (identical twins, inbred mice)
Allograft – transfer of tissue between genetically different members of the same species
Xenograft – transfer of tissue between members of a different species
Laws of Transplantation
(1) Syngrafts are accepted.
(2) Allografts are rejected.
(3) Grafts from an inbred parental strain animal to an F1 hybrid are accepted, but grafts from an F1 animal to a parental strain animal are rejected.
(4) Grafts from animals of the F2 generation, or subsequent generations, are accepted by F1 animals.
(5) Grafts from inbred parental strain animals are accepted by some F2 animals, but are rejected by others.
MHC Restriction and Recognition
MHC Restriction: Each T cell is restricted to binding specific combinations of foreign peptide/MHC complex
Alloreactive T cells (cross-reactive allospecificity): have the ability to respond to the cells of a genetically distinct individual of the same species (ie self-MHC restricted T cells can also recognize allogeneic MHCs)
- For a T cell specific for foreign antigen "X" and MHC "HLA-B27":
- T cell will bind to "X" presented on "HLA-B27"
- T cell will not bind to "Y" presented on "HLA-B27"
- T cell will not bind to "X" presented on "HLA-B2"
Allospecific T cells express:
- Involve a greater fraction of the circulating T cell population than do responses to typical microbial antigen
- Allogeneic responses include reactivity with intact allogeneic MHC Ag, peptides derived from allogeneic MHC Ag, and peptides derived from proteins other than MHC proteins
The recognition of minor H antigen corresponds to the situation where the donor and recipient express one or more MHCs in common, but the donor MHCs have bound peptides that correspond to polymorphic regions of donor proteins, such that donor and recipient differ in these amino acid sequences
- Direct recognition: recognize self or allogeneic peptides in association with intact allogeneic MHCs
- Indirect recognition: recognize foreign (allogeneic) peptides in association with self MHCs
- Thus, T cell recognition of minor H antigen can occur at the surface of either donor or recipient APC
Both antibody or T cells can contribute to graft rejection
Grafts expressing only class I MHC, only class II MHC, or only minor H differences can be rejected
Types of graft rejection:
graft rejection manifests features expected of all immune responses: specificity and memory
- (1) Hyperacute rejection – preformed antibody specific for antigen expressed by allogeneic kidney grafts; occurs within 24 hrs
- also occurs in rejection of vascularized xenografts
- (2) Accelerated rejection – comparable to 2nd set rejection, where the recipient has already been exposed to these Ag; Mediated by T cells and occurs within 5 days
- (3) Acute rejection – rejection of renal allograft mediated by T cells; occurs within a few weeks to months
- (4) Chronic rejection – long-term solid organ graft rejection mediated by both humoral and cellular immunity
- (5) graft vs host disease (GVHD) – transplantation of immunocompetent cells from donor to recipient during allogeneic stem cell transplantation (bone marrow transplants), resulting in cells of the graft rejecting the donor
- due to T cells in the donor inoculum
- decreased incidence of GVHD in recipients given allogeneic bone marrow depleted of mature T cells
approaches to eliminating graft rejection:
matching of donor and recipient for HLA antigen
generalized suppression of immune (especially T cell) responsiveness
induction of clonally-specific nonresponsiveness
- 2nd set response: exposure to a graft from one strain will result in more rapid rejection of a 2nd graft from that strain
Methods for Typing HLA Antigens
microlymphocytotoxicity assay – involves the use of HLA-specific antibodies obtained from multiparous women, characterized with lymphocytes of known antigenic expression
in antibody screening, the reactivity of recipient serum with a panel of cells from genetically diverse individ is determined
crossmatching is important for patients awaiting cadaveric renal transplantation, as a positive crossmatch between serum from a particular potential recipient and cells from a donor will exclude that recipient form receiving an organ from that donor
sequence specific oligonucleotide probes or sequence specific PCR primers have been developed for doing HLA typing, and are routinely used for typing of class II alleles (also being adapted for HLA class I typing)
more accurate, more robust, more reliable as compared to serological testing
the highest resolution method for HLA typing is determination of nucleotide sequences of all relevant genes
conceivable for use if advances increase the speed and reduce the cost of such a technique
- in this assay, if a given antibody reacts with cells of a given individual, complement is fixed, lysing the cells
- dead cells are detected with vital dye such as trypan blue or eosin
- fraction of dead cells is determined for each pair of antibody and cells
- when cells of unknown HLA type are reacted with many previously characterized sera, covering all of the known HLA allelic specificities, then the reactivity pattern permits the assignment of the cell donor’s HLA phenotype
- this assay is used for the crossmatch (recipient serum is tested for reactivity with donor cells) and in antibody screening of potential recipients