Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and man.

Publication Type:

Journal Article


Blood (2016)


One of the central challenges of transplantation is the development of alloreactivity despite the use of multi-agent 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 non-human primate model to interrogate the transcriptional signature of T cells during Breakthrough Acute GVHD that occurs in the setting of clinically-relevant immune suppression and compared this to the Hyperacute GVHD, that develops in unprophylaxed or sub-optimally prophylaxed transplant recipients. Our results demonstrate the complex character of the alloreactivity that develops during ongoing immunoprophylaxis and identify three key transcriptional hallmarks of Breakthrough Acute GVHD that are not observed in Hyperacute GVHD: (1) T cell persistence rather than proliferation and (2) Evidence for highly inflammatory transcriptional programming and (3) Skewing towards a Th/Tc17 transcriptional program. Importantly, the gene co-expression profiles from human HCT recipients who developed GVHD while on immunosuppressive prophylactic agents recapitulated the patterns observed in NHP, and demonstrated an evolution towards a more inflammatory signature as time post-transplant progressed. These results strongly implicate the evolution of both inflammatory and IL17-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 post-transplant despite immunoprophylaxis and to develop evidence-based strategies for effective treatment of this disease.