Cai, X

Cooper, MH

Fung, JJ

Markus, PM

Starzl, TE

English

PubMed

Name not available

Prolonged prevention of acute graft-versus-host disease after allogeneic bone marrow transplantation by donor pretreatment using FK 506

D-Scholarship@Pitt

--- ' ,----,----Prolonged Prevention of Acute Graft-Versus-Host Disease After Allogeneic Bone Marrow Transplantation by Donor Pretreatment Using FK 506 M.H. Cooper, P.M. Markus, X. Cai, T.E. Starzl, and J.J. Fung ACUTE graft-versus-host disease (GVHD) is a sys-temic manifestation of activation of normal allodis-parate transplanted lymphoid cells to recipient epithelial target organs. In clinical bone marrow transplantation (BMT) between HLA identical siblings, acute GVHD occurs in up to 50% of cases, 1 many times during the early posttransplant period. It has recently been shown that FK 506 is superior to cyclosporine (Cy A) for the prevention of lethal acute GVHD after allogeneic bone marrow trans-plantation in the rat. 2 It is known that FK 506 compared to Cy A in vitro has a higher potency with regard to its effects on the early events of T-cell activation. particularly if FK 506 is present at or before the time of antigenic stimulation. We have examined whether a single treatment of the allogeneic donor, either alone, in combination with contin-uous recipient prophylactic therapy, or with discontinuous recipient therapy, could significantly prolong the GVHD-free interval and subsequent overall survival after fully allogeneic bone marrow transplantation in our previously described animal model. 2 MATERIALS AND METHODS Animals Male Lewis (RT-Il) and ACI (RT-la) rats (Harlan Sprague Daw-ley, Indianapolis, Ind), aged 7 to 9 weeks. were used in all experiments. Animals were maintained in a laminar flow caging system (Thorens Caging Systems) and given acidified water as described previously. 2 BMT and Assessment of GVHD BMT was performed according to a protocol previously described at our institution.2 Briefly, bone marrow and spleen cells were prepared as single-cell suspensions. Sixty million ACI bone mar-row and 30 million spleen cells were injected via the penile vein into lethally irradiated (1000 rad) Lewis recipients. All animals received antibiotics in the immediate posttransplant period. All animals were observed daily for evidence of GYHD. Clinical and histological criteria (as assessed by weekly ear biopsies) used for the diagnosis of GYHD. have been described in a previous study from our institution.2 Immunosuppression FK 506 was a gift from Fujisawa Pharmaceutical Co (Osaka, Japan). The powder with carrier solvent was diluted in normal saline for 1M injections. FK 506 was given once a day. unless otherwise specified. Study Design and Statistical Analysis The allocation of groups is shown in Table I. Groups of animals received an allogeneic bone marrow,grllfi from donor animals that . . "D~ Table 1. Group Assignments ShOWing Donor and Recipient Treatments Donor Recipient Treatment Treatment Group n (Days) (Days) A 10 0 H B 8 0 3-8 C 8 0 D 10 H E 8 3-8 F 8 0 0 All FK 506 doses were 1 mglkg per day 1M. had either received either one dose of FK 506 or no drug. The respective recipients received either no additional therapy, a course of FK 506 starting on day 0, or a course of FK 506 starting on day 3. The GYHD-free interval and survival were compared between groups. Statistical analysis was performed using Stu-dent's t test. P < .05 was considered significant. RESULTS The mean GVHD-free interval and survival are shown in Table 2. The addition of one dose of FK 506 (I mg/kg) significantly prolonged the mean GVHD-free survival and survival when compared to no donor pretreatment (P = .01). When donor pretreatment was added to a 0- to 6-day course of FK 506 (l mg/kg) given to the recipient, and compared to a recipient 0- to 6-day course of FK 506 alone. the GVHD-free interval was extended from 42 to 60 days (P < .(01). When donor pretreatment was combined with a 3- to 8-day course of FK 506 given to the recipient, the GYHD-free interval was again prolonged in comparison to a recipient course alone, although by a smaller degree than when the recipients had received a 0- to 6-day course of therapy. When the recipients received no therapy, the addition of one dose of FK 506 given to the donor was, by itself, sufficient to prolong the GVHD-free interval. The differences in mean GVHD-free intervals between these From the Department of Surgery, Division of Transplantation, University of Pittsburgh School of Medicine, Pittsburgh, Pennsyl-vania. Supported by NIH Research Grant No. DK29961, National Institutes of Health, Bethesda, Maryland. Address reprint requests to Dr M.H. Cooper, Department of Surgery, Division of Transplantation, 15th Floor, Biomedical Sci-ence Tower, Pittsburgh, PA 15232. © 1991 by Appleton & Lange 0041-1345/911$3.00/+0 3238 Transplantation Proceedings, Vol 23, No 6 (December), 1991: pp 323!h'3239 PREVENTION OF ACUTE GVHD AFTER BMT Table 2. Mean Time to GVHD and Mean Survival Mean Time to GVHD Mean Survival Group (Days Post-BMT) (Days Post-BMT) A 42.0::!: 3.1 45.0::!: 4.6 B 45.0 ± 4.6 48.0 ± 5.1 C 12.7 ± 1.3 18.8 :t 0.87 0 6O.0::!: 5.9 64.0::!: 6.13 E 52.0::!: 4.8 59.0:t 6.2 F 10.O::!: 1.1 15.0::!: 1.7 All values are means:!: SEM. groups were reflected in the differences of mean survival times (Table 2). DISCUSSION In this study, we have shown that the addition of one dose of the immunosuppressant, FK 506, to an allogeneic bone marrow donor can significantly prolong the mean GVHD-free interval after allogeneic BMT. This donor pretreat-ment therapy gives better results when combined with a recipient course of FK 506 from days 0 to 6 rather than 3 to 8, and it may be that continuous therapy is more beneficial than fragmented prophylaxis. The most likely explanations for these observations are drug carry-over effects or residual inhibitory affects on T cells. Drug carry-over effects are the most likely explanation, since it 3239 became known that FK 506 is difficult to remove from in vitro systems.3 The alternative possibility is a direct effect on the donor cells prior to BMT. Perhaps it is possible that this question could be addressed by measuring donor blood levels of FK 506 and waiting until these return to zero. This would then eliminate carry-over effects and allow assessment of whether pretreatment of the cells gives additional immunosuppressive activity. There is also the prospect of recipient pretreatment for solid organ allografting, and whether this is valuable in reducing incidence or severity of allograft rejection. FK 506 has been shown to be effective in delaying the onset of rejection in the heterotopic heart allograft model in the rat. 4 Therefore, we conclude that pretreatment of an allogeneic donor prior to BMT with FK 506 can prolong the GVHD-free interval and survival, particularly when this treatment is combined with continuous recipient ther-apy. REFERENCES I. Storb R, Thomas ED: Immunol Rev 71:77, 1983 2. Markus PM, Cai X. Ming W, et al: Transplantation (in press) 3. Cooper MH. Gregory S, Thomson AW: Transplant Proc 23:(this issue), 1991 4. Murase N, Todo S. Lee P-H: Transplant Proc 19:71, 1987 

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Prolonged prevention of acute graft-versus-host disease after allogeneic bone marrow transplantation by donor pretreatment using FK 506

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