Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease

Abstract

The therapeutic benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are derived from the graft-versus-leukemia (GvL) effects of the procedure. There is a strong association between the GvL effects and graft-versus-host disease (GvHD), a major life-threatening complication of allo-HSCT. The limiting of GvHD while maintaining the GvL effect remains the goal of allo-HSCT. Therefore, identifying optimal therapeutic targets to selectively suppress GvHD while maintaining the GvL effects represents a significant unmet medical need. We demonstrate that the dual inhibition of interferon gamma receptor (IFNγR) and interleukin-6 receptor (IL6R) results in near-complete elimination of GvHD in a fully major histocompatibility complex–mismatched allo-HSCT model. Furthermore, baricitinib (an inhibitor of Janus kinases 1 and 2 [JAK1/JAK2] downstream of IFNγR/IL6R) completely prevented GvHD; expanded regulatory T cells by preserving JAK3-STAT5 signaling; downregulated CXCR3 and helper T cells 1 and 2 while preserving allogeneic antigen-presenting cell–stimulated T cell proliferation; and suppressed the expression of major histocompatibility complex II (I-Ad), CD80/86, and PD-L1 on host antigen-presenting cells. Baricitinib also reversed established GvHD with 100% survival, thus demonstrating both preventive and therapeutic roles for this compound. Remarkably, baricitinib enhanced the GvL effects, possibly by downregulating tumor PD-L1 expression.

Targeting JAK/STAT pathway in Takayasu’s arteritis

“…One can conclude that any JAKinib would have an equivalent effect on T cells in the treatment of TAK. However, baricitinib seems to be more efficient than ruxolitinib to increase Tregs proportion among human primary T cells, through preservation of JAK3/STAT5 signalling pathway 23. These results raise the question of whether a specific JAKinib should be preferentially indicated in the TAK treatment.…”

Janus kinase inhibitors: A therapeutic strategy for cancer and autoimmune diseases

“…Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is helpful in the management of hematological malignancies and derived from graft‐versus‐leukemia (GvL) outcomes, which are modulated by T cells existing in the donor graft. On the other hand, the same donor T cells can also modulate the graft‐versus‐host disease (GvHD), that it is the main cause of death among allo‐HSCT recipients (Choi et al, 2018). It is demonstrated that baricitinib inhibits IFN‐γR and IL‐6R signaling and prevents GvHD with 100% survival, expanded regulatory T cells and inhibited the expression of MHC II (Choi et al, 2018).…”

“…On the other hand, the same donor T cells can also modulate the graft‐versus‐host disease (GvHD), that it is the main cause of death among allo‐HSCT recipients (Choi et al, 2018). It is demonstrated that baricitinib inhibits IFN‐γR and IL‐6R signaling and prevents GvHD with 100% survival, expanded regulatory T cells and inhibited the expression of MHC II (Choi et al, 2018). Also, baricitinib conserves the GvL effects possibly through downregulating tumor PD‐L1 expression (Choi et al, 2018).…”

“…It is demonstrated that baricitinib inhibits IFN‐γR and IL‐6R signaling and prevents GvHD with 100% survival, expanded regulatory T cells and inhibited the expression of MHC II (Choi et al, 2018). Also, baricitinib conserves the GvL effects possibly through downregulating tumor PD‐L1 expression (Choi et al, 2018).…”

Dawn of Monitoring Regulatory T Cells in (Pre-)clinical Studies: Their Relevance Is Slowly Recognised

“…Clinically, also effects on Tregs (i.e., frequency) were investigated and a potential association between Tregs and the clinical response was explored. However, the amount of data presented in published studies (i.e., on local and systemic Treg frequency and functionality in mice and men, but also in vitro) was much more extensive than present in the dossier reports, although for one of the JAK inhibitors only one literature study was available (151)(152)(153)(154)(155)(156)(157)(158).…”