Interleukin-6 Modulates Graft-versus-Host Responses after Experimental Allogeneic Bone Marrow Transplantation

Abstract

Purpose: The graft-versus-tumor (GVT) effect is a potent form of immunotherapy against many hematologic malignancies and some solid tumors. The beneficial GVT effect after allogeneic bone marrow transplantation (BMT) is tightly linked to its most significant complication, graft-versus-host disease (GVHD). The role of interleukin-6 (IL-6) after allogeneic BMT is not well understood. This study used a series of complementary knockout and antibody blockade strategies to analyze the impact of IL-6 in multiple clinically relevant murine models of GVHD and GVT.Experimental Design: We examined the effect of the source of IL-6 by analyzing the role IL-6 deficiency in donor T cells, donor bone marrow or in host tissues. We confirmed and extended the relevance of IL-6 deficiency on GVHD and GVT by treating BMT recipients with anti-mouse IL-6 receptor (IL-6R), MR16-1.Results: Deficiency of IL-6 in donor T cells led to prolongation of survival. Total inhibition of IL-6 with MR16-1 caused an even greater reduction in GVHD-induced mortality. The reduction in GVHD was independent of the direct effects on T effector cell expansion or donor regulatory T cells. GVT responses were preserved after treatment with MR16-1.Conclusion: MR16-1 treatment reduced GVHD and preserved sufficient GVT. Tocilizumab, a humanized anti-IL-6R monoclonal antibody (mAb), is approved in several countries including the United States and European Union for the treatment of rheumatoid arthritis and other inflammatory diseases. Blockade of IL-6 with anti-IL-6R mAb therapy may be testable in clinical trials as an adjunct to prevent GVHD in BMT patients without a significant loss of GVT.

Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease

“…41 Low platelet count is associated with poor survival in cGVHD 42 ; however, in the cohort reported here, elevated platelet counts were significantly associated with ScGVHD. This finding may reflect the role of platelets as acute phase reactants 40 ; however, elevated circulating platelet counts and overexpression of the collagen I receptor on platelets has been found in patients with systemic sclerosis. 43 Patients with systemic sclerosis demonstrate enhanced platelet aggregation and release of growth factors, such as PDGF, TGF-␤, ␤-fibroblast growth factor, and connective tissue growth factor, which may stimulate the synthesis of collagens and other matrix proteins.…”

“…39 Although tissue deposition of complement would be expected to lead to lower levels of circulating complement, the inflammatory disease state of GVHD may theoretically result in a net increase in the synthesis of complement in response to cytokines such as IL-6. 40 Complement has been shown to stimulate other fibrotic processes, such as cirrhosis, by the expression of complement receptors on myofibroblasts in the liver. 41 Low platelet count is associated with poor survival in cGVHD 42 ; however, in the cohort reported here, elevated platelet counts were significantly associated with ScGVHD.…”

Cytokines in Graft-versus-Host Disease

“…Initiation of Th17 development is triggered by IL-6 and TGF-b and is associated with transcriptional activation of RORgt after phosphorylation of STAT3, as well as with the secretion of IL-17, IL-21, and IL-22. There is an increasing appreciation for the role that Th17 cells play in determining the severity of GVHD (65), with a particular role for IL-6 becoming apparent (66,67). Recently, our group demonstrated the importance of this effect in cohorts in which IL-6 inhibition represents a potentially effective therapeutic strategy to reduce the severity of aGVHD in clinical stem cell transplantation (45).…”

State-of-the-art acute and chronic GVHD treatment

“…IL6 increases circulating TH1 and TH17 T cell subsets and suppresses Tregs. In preclinical studies IL6 blockade has been associated marked responses in GVHD [161,162]. Tocilizumab when used for steroid-refractory GVHD has shown responses and prophylaxis with tocilizumab is associated with markedly reduced GVHD [163].…”