CCR1 Is Required for Treg-Mediated Protection From Lethal Acute Graft-Versus-Host Disease.
Authors: Carlson Michael J , Coghill James M. , West Michelle L. , Panoskaltsis-Mortari Angela , Blazar Bruce R. , Serody Jonathan S 
Published: October 2019

Abstract 1337

Poster Board I-359

INTRODUCTION

Graft-versus-host disease (GVHD) is a major complication following allogeneic bone marrow transplantation (BMT). Despite advances in understanding the etiology of GVHD it remains a formidable obstacle to the widespread application of BMT. A number of studies have demonstrated that T regulatory (Treg) cells represent a potential therapy for GVHD as Tregs have been shown to inhibit GVHD while preserving the beneficial graft-versus-leukemia (GVL) effect. Numerous groups, including our own, have demonstrated the importance of T cell migration in the pathology of GVHD. Following conditioning, donor T cells migrate to secondary lymphoid tissues. Once activated in the lymphatics, T cells migrate to GVHD target organs including; the skin, liver, lung and the gastrointestinal (GI) tract in response to the local production of chemokines. Disruption of chemokine-chemokine receptor interactions has been demonstrated to affect the pathology of GVHD. Previously, we have shown that Tregs lacking the chemokine receptor CCR5, which binds CCL3, CCL4, and CCL5, do not protect animals from lethal GVHD as well as WT Tregs, due to their impaired migration to the liver and lung. Thus, a greater understanding of the function of chemokine receptors on Tregs is important in deciphering how Tregs function and whether targeting these cells to lymphoid tissue or GVHD target organs would be preferable for treating patients in clinical trials.

METHODS

We utilized a parent into F1 haploidentical model to assess the role of CCR1 in Treg-mediated protection from GVHD. Here we demonstrate Tregs lacking CCR1, another receptor for CCL3 and CCL5, were unable to protect animals against lethal acute GVHD. While 67% of B6D2 recipients given 1×106 WT Tregs supplemented with 5×106 WT T cells and 3×106 B6 T cell-depleted BM cells survived, only 15% of the recipients given CCR1−/− Tregs survived (p < 0.03; Fisher's exact test). B6D2 recipient mice given WT Tregs had significantly reduced clinical scores for GVHD compared to B6D2 recipients of CCR1−/− Tregs (p <0.05) with elevated GVHD scores starting on day 28 post-transplant. Histopathology revealed significantly worse pathology in the liver (p < 0.03) and colon (p < 0.05) of CCR1−/− Treg recipients vs. WT Treg recipients. In vitro analysis demonstrated that CCR1−/− Tregs were capable of suppressing T cell responses to allo-antigen equally as well as WT Tregs, and CCR1−/− Tregs attained a normal activation phenotype. Interestingly, preliminary experiments suggested that CCR1−/− Tregs migrated to and/or expanded in GVHD target organs to a similar extent as WT Tregs.

CONCLUSIONS

Treg expression of CCR1 is required for the inhibition of GVHD. Tregs lacking CCR1 led to significantly more tissue destruction in the liver and colon, two predominant sites of GVHD pathology. Of interest, the migration of CCR1−/− Tregs to GVHD target organs and secondary lymphoid tissues did not appear to be compromised suggesting that CCR1 may be required for the function of Tregsin vivo.

Disclosures

No relevant conflicts of interest to declare.