Journal of immunology (Baltimore, Md. : 1950)Sep 24, 2025

Lack of glucagon-like peptide-1 receptor signaling worsens blood stem cell transplant rejection in mice

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jan 20, 2026

Abstract

GLP1R deficiency in recipient mice leads to a profound increase in graft failure following MHC-mismatched hematopoietic stem cell transplantation.

Mice lacking GLP1R experienced significantly greater weight loss and earlier mortality after MHC-mismatched transplants.
GLP1R knockout mice showed reduced donor chimerism compared to wild-type mice in MHC-mismatched conditions.
The observed phenotype in GLP1R knockout mice is associated with early graft rejection rather than graft-versus-host disease.
Depletion of CD90+ recipient T cells prior to transplantation improved engraftment outcomes in GLP1R knockout mice.
These findings suggest a role for GLP1R signaling in regulating immune responses that affect graft acceptance.

Simplified

Graft failure (GF) following hematopoietic stem cell transplantation (HSCT) remains a major complication particularly in the setting of human leukocyte antigen (HLA)-mismatched grafts where residual host lymphocytes can drive immune-mediated rejection. While strategies to mitigate GF have been explored, such as intensified conditioning or donor T cell supplementation, these approaches carry significant risks, including increased toxicity and graft-versus-host disease (GVHD). Recent studies have highlighted the glucagon-like peptide-1 receptor (GLP1R) as a critical regulator of immune homeostasis, yet its role in HSC engraftment remains unexplored. Here, we demonstrated that GLP1R deficiency in recipient mice leads to a profound increase in GF following MHC-mismatched allogeneic HSCT. Although GLP1R knockout (GLP1RKO) and wild-type (WT) mice exhibited comparable survival and engraftment following syngeneic or minor antigen-mismatched transplants, GLP1RKO mice undergoing MHC-mismatched HSCT experienced significantly greater weight loss, earlier mortality, and reduced donor chimerism. Histologic and cytokine analyses confirmed that this phenotype is not driven by GVHD, but rather by early graft rejection. Depletion of CD90+ recipient T cells prior to transplantation rescued engraftment in GLP1RKO mice, further supporting a model in which GLP1R signaling restrains host lymphocyte-mediated graft rejection. These findings identify GLP1R as a novel regulator of allogeneic HSC engraftment and suggest that GLP1R agonists, widely used for metabolic disorders, may have therapeutic potential in preventing HSC graft rejection. Given the lack of targeted interventions for HSC graft rejection, further studies are warranted to investigate GLP1R-directed therapies in the context of allogeneic HSCT.

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Lack of glucagon-like peptide-1 receptor signaling worsens blood stem cell transplant rejection in mice

Abstract

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