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Prepublished online as a Blood First Edition Paper on May 31, 2002; DOI 10.1182/blood-2002-04-1082.
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Blood, 1 October 2002, Vol. 100, No. 7, pp. 2642-2649
TRANSPLANTATION
Interleukin 7 worsens graft-versus-host disease
Manoj L. Sinha,
Terry J. Fry,
Daniel H. Fowler,
Georgina Miller, and
Crystal L. Mackall
From the Pediatric Oncology Branch, Experimental
Transplantation and Immunology Branch, National Cancer Institute, and
Veterinary Resources Program, National Institutes of Health, Bethesda,
MD.
Impaired immune reconstitution has moved to the forefront of
clinical problems limiting progress in allogeneic bone marrow transplantation (BMT). The identification of therapies that can enhance
immune reconstitution by increasing thymopoiesis is critical to solving
this problem. Interleukin 7 (IL-7) is the most potent thymopoietic
cytokine identified thus far. To study the effects of IL-7 on immune
reconstitution and graft-versus-host disease (GVHD) following
allogeneic BMT, we administered recombinant human IL-7 (rhIL-7) in a
murine parent into an F1 model. Results showed that rhIL-7 therapy
lowered the "threshold" T-cell dose required to induce both
clinical signs of GVHD as well as lethal GVHD. Histologic analysis of
GVHD target tissues revealed that rhIL-7 increased the degree of
inflammation and tissue damage observed at all T-cell doses studied,
but did not change the pattern of organs affected or the histologic
appearance of the GVHD within target organs. In addition, we evaluated
the capacity for rhIL-7 to enhance thymopoiesis in the setting of
allogeneic T cell-depleted (TCD) and T-cell-replete BMT. We observed
that rhIL-7 therapy enhanced thymic function in TCD allogeneic BM
transplant recipients, but not in animals that received even
modest doses of T cells presumably due to thymic toxicity of the
graft-versus-host reaction. Thus, caution must be exercised as IL-7 is
developed clinically as an immunorestorative agent for use in the
setting of allogeneic BMT. These results suggest that use of IL-7
should be limited to the setting of TCD BMT to obtain the greatest
benefit on immune competence with the least toxicity.
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