Tim-3/Gal-9 and B7-H3 act as negative regulators of graft versus host disease

Abstract

Allogeneic HSCT is a treatment option for many malignant and nonmalignant hematologic disorders with potential to treat a variety of diseases. However, a very significant limiting factor for its use is the high risk of graft versus host disease (GVHD) that limits its efficacy and use in broader applications. GVHD occurs when there is an antigen disparity between the donor and the recipient. This disparity leads to activation of donor T cells that migrate to GVHD target organs and mediate damage. Current therapies involve broad immune suppression that can lead to toxicity and increased relapse rates for cancers. By elucidating the positive and negative regulatory pathways in GVHD biology, new therapeutic targets can be identified for translation into the clinic. Research presented here investigates the role of the Tim-3/gal-9 pathway as well as the B7-H3 pathway in acute GVHD. Recipients of Tim-3 deficient donor T cells had accelerated GVHD lethality while Gal-9 transgenic recipients had a reduced GVHD lethality. Paradoxically, recipients of Tim-3 deficient and CD25 depleted donor T cells had a significantly reduced GVHD lethality with an associated reduced pathology in the colon. CD25-depleted Tim-3-/- donor T-cells underwent increased activation-induced cell death due to increased IFN-γ production. B7- H3 deficient recipients had accelerated GVHD lethality and had increased pathology in the colon. Interestingly, recipients of B7-H3 deficient donor T cells also had an accelerated GVHD lethality, with increased T-cell proliferation in the spleen as well as increased pathology in the colon. This work identifies B7-H3 as a negative regulator of acute GVHD.