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*
University of Minnesota Cancer Center and Department of Pediatrics, Division of Bone Marrow Transplantation, Minneapolis, MN 55455;
Division of Clinical Research, Fred Hutchinson Cancer Research Center Department of Medicine, Seattle, WA 98195;
Department of Microbiology, Dartmouth Medical College, Hanover, NH 03756;
§
Department of Ophthalmology, Louisiana State University Medical Center, New Orleans, LA 70112; and
¶
Science Applications International-Frederick and the Laboratory of Leukocyte Biology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702
Delayed lymphocyte infusions (DLIs) are used to treat relapse
occurring post bone marrow transplantation (BMT) and to increase the
donor chimerism in recipients receiving nonmyeloablative conditioning.
As compared with donor lymphocytes given early post-BMT, DLIs are
associated with a reduced risk of graft-vs-host disease (GVHD). The
mechanism(s) responsible for such resistance have remained incompletely
defined. We now have observed that host T cells present 3 wk after
lethal total body irradiation, at the time of DLI, contribute to
DLI-GVHD resistance. The infusion of donor splenocytes on day 0, a time
when host bone marrow (BM)-derived T cells are absent, results in
greater expansion than later post-BMT when host and donor BM-derived T
cells coexist. Selective depletion of host T cells with anti-Thy1
allelic mAb increased the GVHD risk of DLI, indicating that a
Thy1+ host T cell regulated DLI-GVHD lethality. The
conditions by which host T cells are required for optimal DLI
resistance were determined. Recipients unable to express CD28 or 4-1BB
were as susceptible to DLI-GVHD as anti-Thy1 allelic mAb-treated
recipients, indicating that CD28 and 4-1BB are critical to DLI-GVHD
resistance. Recipients deficient in both perforin and Fas ligand but
not individually were highly susceptible to DLI-GVHD. Recipients that
cannot produce IFN-
were more susceptible to DLI-GVHD, whereas those
deficient in IL-12 or p55 TNFRI were not. Collectively, these data
indicate that host T cells, which are capable of generating antidonor
CTL effector cells, are responsible for the impaired ability of DLI to
induce GVHD. These same mechanisms may limit the efficacy of DLI in
cancer therapy under some conditions.
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