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 Blood, 9 April 2009, Vol. 113, No. 15, pp. 3612-3619.
Prepublished online as a Blood First Edition Paper on February 10, 2009; DOI 10.1182/blood-2008-07-168419.

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TRANSPLANTATION

Paradoxical effects of IFN-{gamma} in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury

Hui Wang1, Wannee Asavaroengchai1, Beow Yong Yeap2, Min-Guang Wang3, Shumei Wang1, Megan Sykes1, and Yong-Guang Yang1

1 Bone Marrow Transplantation Section, Transplantation Biology Research Center, and 2 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston; and 3 Lower Columbia Pathologists, Longview, WA

Interferon-{gamma} (IFN-{gamma}) inhibits graft-versus-host disease (GVHD) in lethally irradiated mice receiving allogeneic hematopoietic cell transplantation (allo-HCT) but promotes lethality in unirradiated and sublethally irradiated recipients. We investigated the role of IFN-{gamma} in GVHD in sublethally irradiated B6D2F1 recipients of B6 allo-HCT. B6D2F1 mice receiving wild-type B6 splenocytes alone died rapidly, whereas those receiving wild-type B6 splenocytes plus marrow survived long-term. Mice in both groups showed rapid elimination of host hematopoietic cells but minimal parenchymal tissue injury. However, mice receiving allo-HCT from IFN-{gamma}–deficient donors died rapidly regardless of whether donor marrow was given, and they exhibited severe parenchymal injury but prolonged survival of host hematopoietic cells. IFN-{gamma} plays a similar role in another model involving delayed B6 donor leukocyte infusion (DLI) to established mixed allogeneic (B6->BALB/c) chimeras. IFN-{gamma} promotes DLI-mediated conversion from mixed to full donor chimerism while attenuating GVHD. Importantly, IFN-{gamma} enhances graft-versus-leukemia (GVL) effects in both models. Our data indicate that previously reported IFN-{gamma}–induced early mortality in allo-HCT recipients is due to augmentation of lymphohematopoietic graft-versus-host reaction (LGVHR) and can be avoided by providing an adequate source of donor hematopoietic stem/progenitor cells. Furthermore, the magnitude of GVL is correlated with the strength of LGVHR, and IFN-{gamma} reduces the potential of this alloreactivity to cause epithelial tissue GVHD.


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