Systems analysis uncovers inflammatory Th/Tc17-driven modules during acute GVHD in monkey and human T cells

Abstract

• The transcriptional networks controlling breakthrough acute GVHD can be mapped, and correlate closely with clinical disease.• Breakthrough acute GVHD is transcriptionally controlled by T-cell persistence, inflammation, and Th/Tc17 skewing.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 graftversus-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. (Blood. 2016;128(21):2568-2579

Th17 plasticity and transition toward a pathogenic cytokine signature are regulated by cyclosporine after allogeneic SCT

“…17,48 In the setting of acute GVHD, a recent study found that acute GVHD breaking through immune suppression was typified by T-cell persistence, as well as pro-inflammatory and Th/Tc17 transcriptional biases. 49 Here, we describe a T-cell lineage highly concordant with these observations, sharing the hallmarks of persistence, highly proinflammatory phenotype, and the Th17 transcriptional program.…”

Combined OX40L and mTOR blockade controls effector T cell activation while preserving T reg reconstitution after transplant

“…However, although sirolimus has several pro-tolerogenic mechanistic advantages, it is still not understood how best to deploy this agent, and it currently remains a second line therapy that is not clinically superior to CNI (5, 6). This lack of clinical superiority is due to a number of factors: First, post-transplant monotherapy with sirolimus, in the absence of adjunctive pre-transplant GVHD prevention (7, 8) is unable to sufficiently control Teff activation and, thus cannot in itself prevent GVHD (3, 9). Further, combination strategies that pair sirolimus with CNI or inhibitors of proliferation (such as mycophenolate mofetil (MMF) or methotrexate) have not improved rates of GVHD (6, 10, 11), likely due to the antagonistic impact of these agents on Treg function.…”

An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition

“…In addition, different surface markers have been described, such as chemokine receptor 6 (CCR6), CD161, CCR4, IL-23R, and CD5L to characterize the Th17 subset (17,18). Several studies have attempted to decipher the role of Th17 in aGvHD (19,20). However, murine models presented conflicting results, as IL-17-KO donor T cells either reduced (21) or exacerbated aGvHD (22).…”