||5R01CA231141-02 Interpret this number
||University Of Tx Md Anderson Can Ctr
||Genetics of Graft-Versus-Host Disease
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for many advanced
hematologic malignancies. Allo-HSCT is associated with significant morbidities and mortality, mainly because of
the graft-versus-host disease (GVHD) caused by donor T cells recognizing antigens present in recipient tissues,
and initiating an alloimmune response resulting in damage to many organs including the skin, GI tract, and liver
in recipient. More than half of all allo-HSCT recipients develop different degrees of GVHD (grade I-IV). About
20% of recipients develop severe GVHD (grade III-IV) that is associated with a very high morbidity and mortality.
The most important factor determining the severity of GVHD is the genetic disparities between donors and
recipients, as is reflected in HLA haplotypes that are routinely checked for donor selection. But even when donors
and recipients are HLA-identical many recipients develop severe GVHD. As a result, non-HLA antigens are
important determinants of acute GVHD. An interesting and unique aspect of GVHD is that it is the consequence
of an interaction between antigens present in one individual with the immune system of another individual. As a
result, genotypes of both donor and recipient, and their interactions affect the pathogenesis of GVHD. To
determine the genetic risk factors for GVHD, in the first aim (discovery phase), we will conduct Genome-Wide
Association Studies (GWAS) in 3,000 patients who underwent allo-HSCT and in their respective donors (6000
DNA samples) that are provided to us by the National Marrow Donor Program (NMDP) and the Center for
International Blood and Marrow Transplant Research (CIBMTR). This part of our grant is approved by the Center
for Inherited Disease Research (CIDR) and will be conducted in their sequencing facility. We expect that 3000
recipients will be stratified into 1200 subjects with moderate to severe acute GVHD (grades II-IV) versus 1800
individuals with none to mild GVHD (grade 0-I). We will also include the existing GWAS and clinical outcome
data on 7047 donor/recipient pairs available from two previous studies to augment our cohort with an estimated
2830 pairs with grade II-IV and 4244 pairs with grade 0-I GVHD, and investigate an association between the
severity of acute GVHD and genotypes in donors or recipients, or mismatch of certain genotypes (other than
HLA). In the second aim, we will validate the association between high risk genotypes detected in the aim 1 and
severe GVHD in 1,750 donors and 1,750 recipients of allo-HSCT, and perform the joint analysis with the
discovery samples (an estimated 4730 pairs with grade II-IV vs 7094 pairs with Grade 0-I GVHD). We will
determine the frequency of 5000 single nucleotide polymorphisms (SNP), that GWAS in the aim 1 showed to be
associated with severe GVHD and correlate it to the severity of GVHD. In the third aim, we will investigate the
functional effect of SNPs detected and validated to be significantly correlated with the severity of acute GVHD
in mixed lymphocyte reaction (MLR), as an Ex vivo surrogate for an alloimmune response.
Kidney Injury in Murine Models of Hematopoietic Stem Cell Transplantation.
, Li D.
, Vasquez H.G.
, You M.J.
, Afshar-Kharghan V.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2019-07-02; , .