One of the central challenges of transplantation is the development of alloreactivity despite the use of multiagent immunoprophylaxis. Effective control of this immune suppression-resistant T-cell activation represents one of the key unmet needs in the fields of both solid-organ and hematopoietic stem cell transplant (HCT). To address this unmet need, we have used a highly translational nonhuman primate (NHP) model to interrogate the transcriptional signature of T cells during breakthrough acute graft-versus-host disease (GVHD) that occurs in the setting of clinically relevant immune suppression and compared this to the hyperacute GVHD, which develops in unprophylaxed or suboptimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify 3 key transcriptional hallmarks of breakthrough acute GVHD that are not observed in hyperacute GVHD: (1) T-cell persistence rather than proliferation, (2) evidence for highly inflammatory transcriptional programming, and (3) skewing toward a T helper (Th)/T cytotoxic (Tc)17 transcriptional program. Importantly, the gene coexpression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution toward a more inflammatory signature as time posttransplant progressed. These results strongly implicate the evolution of both inflammatory and interleukin 17-based immune pathogenesis in GVHD, and provide the first map of this evolving process in primates in the setting of clinically relevant immunomodulation. This map represents a novel transcriptomic resource for further systems-based efforts to study the breakthrough alloresponse that occurs posttransplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease.
Bibliographical noteFunding Information:
The authors gratefully acknowledge the technical assistance of Natalia Kozyr, the veterinary care provided by Elizabeth Strober, Joe Jenkins, Annie Torrence, Keith Vogel, and Jennifer Lane, in addition to the services provided by both the Vanderbilt Technologies for Advanced Genomics and the Oregon Health and Science University Gene Profiling Shared Resource. The authors are also grateful to Felix Wu and Jill Mesirov at the Broad Institute for their assistance with the constellation mapping software. This work was supported by Yerkes National Primate Research Center base grant RR00165. The Washington National Primate Research Center at the University of Washington support was funded through the Office of Research Infrastructure Programs at the National Institutes of Health (NIH), Office of the Director (OD) grant P51 OD 010425. Funding was also provided through an Emory University Atlanta Clinical and Translational Science Institute pilot grant (E.K.W.), NIH National Heart, Lung, and Blood Institute (NHLBI) 2 R01 HL56067, National Institute of Allergy and Infectious Diseases (NIAID) R01 AI 34495 and P01 AI 056299 (B.R.B.), NHLBI 5 R01 HL095791, NIAID 5U19-AI051731 (L.S.K.), and Bristol-Myers Squibb (L.S.K.).
© 2016 by The American Society of Hematology.