Therapeutic Benefit of Bortezomib on Acute Graft-versus-Host Disease Is Tissue Specific and Is Associated with Interleukin-6 Levels

Abstract

Bortezomib, a proteasome inhibitor capable of direct anti-tumor effects, has been shown to prevent acute graft-versus-host disease (aGVHD) when administered in a short course immediately after bone marrow transplantation (BMT) in mice. However, when given continuously, CD4+ T cell mediated gastrointestinal tract damages increase GVHD mortality. To investigate the protective effects of bortezomib on other organs, we have used a CD8 dependent aGVHD model of C3H.SW donor T cells engrafted into irradiated C57BL/6 recipients (minor MHC mismatch), which lack significant gut GVHD. Our data in this model show that bortezomib can be given continuously to prevent and treat aGVHD mediated by CD8+ T cells, but this effect is organ-specific such that only skin, but not liver, protection was observed. Despite the lack of hepatic protection, bortezomib still significantly improved survival primarily due to its skin protection. Reduced skin GVHD by bortezomib was correlated with reduced serum and skin IL-6 levels. Administration of a blocking IL-6 antibody in this model also resulted in similar cutaneous GVHD protection. These results indicate that bortezomib or blockade of IL-6 may prevent CD8+ T cell mediated cutaneous aGVHD.

Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice

“…Organ-specific effects may be associated with the effects of neddylation pathways on donor T cells, particularly on chemokine receptor expression. We previously showed that inhibiting proteasome in T cell subsets with bortezomib can decrease CXCR3 expression on T cells [27], and CXCR3 has been shown to affect skin homing. Therefore, it is possible that neddylation also can affect the expression of chemokine receptors, resulting in organ-specific protection effects.…”

“…Bortezomib is known to preferentially provide therapeutic effects in the skin, but not in the liver or GI tract [9,27]. We tested pevonedistat in a small range of dosages (data not shown), and the dosages and administration schedule need to be carefully evaluated for translation into clinical use.…”

Successful treatment of refractory pure red cell aplasia with bortezomib after allogeneic haematopoietic cell transplantation in a patient with alpha‐beta subcutaneous panniculitis‐like T cell lymphoma

“…In addition, beneficial effects of proteasome inhibition on the prevention and treatment of acute and chronic GVHD (Li et al, 2013;Herrera et al, 2014;Pai et al, 2014aPai et al, ,2014b, and the growing knowledge of its anti-cancer effects in lymphoid B and T cell malignancies warrants expanded exploration of using bortezomib as well as next generation proteasome inhibitors in this field. We believe bortezomib to be the cause of the patient's rapidly recovered haemoglobin and feel this is a promising, well tolerated regimen which may benefit others in refractory red cell aplasia following ABO mismatched allo-HCT.…”

Advances and challenges in immunotherapy for solid organ and hematopoietic stem cell transplantation

“…Pre-clinical mouse work with the FDA-approved proteasome inhibitor bortezomib demonstrated that it is a potent inhibitor of alloreactive T cells, and that bortezomib treatment reduced acute GVHD without affecting GVT (50, 51). In addition, one of the mechanisms by which bortezomib reduced GVHD severity was by diminishing production of the inflammatory cytokine IL-6 (discussed above).…”