A number of non HLA genetic factors influence transplant outcome and often need to be taken into account during donor selection. These non HLA genetic factors include Minor Histocompatibility Antigens, MICA and MICB, KIR genes and cytokine genes.
Minor Histocompatibility Antigens
Minor histocompatibility antigens are target for cytotoxic T lymphocytes (CTL’s) and mismatching them can lead to GvHD and to rejection depending on the direction of the mismatch. In studies of HLA matched stem cell transplantation, male recipients of female stem cells had the lowest risk of relapse and greatest risk of GVHD, suggesting that minor histocompatibility antigens encoded by genes on the Y chromosome contributes a GVL effect. Female recipients of male stem cells have an increased risk of activating T cells and developing antibody reactivity against HY antigens leading to rejection.
On the other hand, some minor histocompatibility antigens, such as HA-1, are expressed on leukaemia cells and on some tumour cells, making them ideal targets for a potential CTL immunotherapy.
MICA & MICB
One study has shown that in a series of well matched HLA-A, B, C, DR, DQ stem cell transplants, a higher rate of grades II – IV acute GvHD was observed in patients mismatched for MICA compared to those matched for MICA. The MICA mismatched patients had more gastrointestinal aGvHD than the matched patients, possibly reflecting the tissue distribution of MIC antigens.
In stem cell transplantation donor versus recipient alloreactivity can potentially be generated in HLA-C allele group and/or HLA-Bw4 group mismatched transplantation. Where the recipient does not possess a HLA class I allele group that the donor inhibitory KIR ligands recognise, the donor KIR receptors ‘sense’ the missing ligand in the recipient and can mediate an allo response given the presence of the right activating signals. The Perugia group showed in a series of studies of haploidentical, T cell depleted stem cell transplants that KIR ligand mismatching in the GvH direction benefitted patients with AML. Patient who received these KIR ligand mismatched transplants had significantly reduced rates of relapse and improved incidents of engraftment.
The Perugia group showed in a series of studies of haploidentical, T cell depleted stem cell transplants that NK cell KIR ligand mismatching in the GvH direction benefitted patients with AML. Patient who received these NK cell KIR ligand mismatched transplants had significantly reduced rates of relapse and improved incidents of engraftment.
In an EBMT study looking at the role of NK cell alloreactivity in over 200 AML patients transplanted with cord blood, KIR ligand mismatching in the GvH direction was shown to be significantly associated with a reduced incidence of relapse and better leukaemia free survival.
T cell replete adult stem cell transplants did not show an improvement in disease free survival in most studies with T cells in the graft being shown to adversely affect reconstitution of KIR bearing NK cells.
Another mechanism of action of KIR ligands in stem cell transplantation is the ‘missing ligand’ model which postulates that in the stem cell transplant setting, donor NK cells bearing KIR receptors for HLA class I antigens missing in the donor and which would therefore normally be hypo responsive, upon transplantation, can become activated and exert an anti-leukemic effect.
The other non HLA genes thought to play a role in haematopoietic progenitor cell transplant outcome are Cytokine genes. The belief that a variable ability to produce pro-inflammatory and other cytokines as a result of polymorphisms in the promoter and other regions of these cytokine genes has lead to many studies attempting to understand the role of cytokine polymorphisms in HSCT. Unfortunately these studies have not lead to a consensus view of the role of cytokine genes in transplant outcome. There is some tentative evidence that transplantation with donors who express genes that make them high producers of TNFα and IL-1 leads to increased GvHD. Levels of cytokine production may also have an influence on susceptibility to infection post transplant.
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