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.
University of Minnesota Ph.D. dissertation. May 2013. Major: Microbiology, Immunology and Cancer Biology. Advisor: Bruce Blazar. 1 computer file (PDF); viii, 105 pages.
Veenstra, Rachelle Graham.
Tim-3/Gal-9 and B7-H3 act as negative regulators of graft versus host disease.
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