PROJECT SUMMARY/ABSTRACT
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for
patients with hematologic malignancies. It is believed that alloreactivity upon HSCT is initiated by lymphoid
cells that express rearranging receptors upon recognizing the alloantigens on the graft. Unlike lymphoid cells,
cells from the innate immune system do not express rearranging receptors and are nonspecifically induced by
“danger” molecules. However, recent studies demonstrated that the innate immune system could specifically
distinguish the non-self graft and subsequently enhance the alloimmune response. Signal regulatory protein a
(SIRPa) is a polymorphic immunoglobulin receptor that is exclusively expressed on the surface of innate cells.
The interaction between SIRPa and its ubiquitously expressed ligand, CD47, suppresses the macrophage's
phagocytic function. As shown in the murine transplant model, mismatches of SIRPa between donor and
recipients can upregulate the allorecognition response. Our group recently investigated the role of SIRPa
variant mismatch in recipients of allo-HSCT from a human leukocyte antigen (HLA)-matched related donors
(MRD) for the treatment of different hematological malignancies. We found that for the first time,
donor/recipient SIRPa mismatch is commonly detected and associated with a significantly increased risk of
chronic graft-versus-host disease (cGVHD) and a lower rate of early relapse (Blood Advances 2021; Frontier in
Immunology 2022). We proposed a large registry-based study to validate our results in allo-HSCT recipients
with MRD, which is one of the most common donor sources in allo-HSCT. The study is approved by the Center
for International Blood and Marrow Transplant Research (CIBMTR) immunobiology working committee.
CIBMTR and the National Marrow Donor Program (NMDP) will facilitate the study by providing scientific and
statistical expertise, as well as associated clinical outcome information and biospecimens. We hypothesize that
the mismatched SIRPa elicits a non-self recognition which will further promote adaptive immunity leading to a
higher risk of cGVHD and a lower risk of relapse. In Aim 1, we will perform a retrospective analysis of the
SIRPa mismatch in allo-HSCT with MRD using the CIBMTR data and specimens. Aim 2 is to determine the
relative clinical significance of SIRPa mismatch in the entire cohort and the subgroups of allo-HSCT. The study
will not only define the clinical role of SIRPa variant mismatch in the allo-HSCT setting but also significantly
advance our knowledge of GVHD/ Graft versus Leukemia (GVL) and the allorecognition of the innate immune
system in the context of stem cell transplant.
