Cai, X

Cooper, M

Fung, JJ

Harnaha, J

Markus, PM

Selvaggi, G

Starzl, TE

Transplantation Proceedings

PubMed

D-Scholarship@Pitt

/ c).. '7C( The Effect of Cyclosporine, Rapamycin and FK 506 the Survival Following Allogeneic Bone Marrow Transplantation P.M. Markus, X. Cai, G. Selvaggi, M. Cooper, J. Hamaha, J.J. Fung, and T.E. Starzt WE have previously reponed that treatment with FK 506 and cyclosporine (Cy A) are effective in revers-ing established acute graft-versus-host disease (GVHD) in an allogeneic rat model. 1 In clinical bone marrow trans-plantation, however, recovery from GVHD has not nec-essarily been associated with prolongation of survival. 2.3 Therefore. we were interested in comparing the immuno-suppressive agents, CyA, rapamycin (RPM). and FK 506, in respect to survival after allogeneic bone marrow and spleen ceU transplantation IBMSPTXl. MATERIALS AND METHODS Induction of Acute GVHD A total of 60 x I W bone marrow and 30 x I W spleen cells from ACI donors were infused IV 2 hours after Lewis (LEW) reCipients had been exposed to 1000 rad total body irradiation (TBll. Animals were assessed for clinical signs of GVHD on a daily basis. GYHD was diagnosed when at least three of the following signs were present: erythematous ear. hyperkeratosis of the footpad, dermatitis, weight loss, unkempt appearance, and diar-rhea. Immunosuppression CyA was obtained from Sandoz Pharmaceuticals (Hanover. NI) and dissolved in intralipid. Rapamycin was a gift from Wyeth· Ayerst Research Laboratories (Princeton. Nn and prepared fresh daily by suspension in 0.2% carboxymethyl-ceUulose and thor· oughly homogenized before administration. FK 506. provided by Fujisawa Pharmaceutical Co (Osaka. Japan). was diluted (with carrier solvent HCO-60 and D-mannitol) in normal saline. Survival was calculated by the life·table method. Comparisons of survival were analyzed using the Wilcoxon signed rank test with unequal variances. Two-tailed P values <.05 were consid-ered statistically significant. Study Design Animals sulfering from GVHD were treated with CyA, RAP, or FK 506 1M on days 12 to 2S post-BMSYIX. Group I was used as irradiation control and received 1000 rad TBI without bone marrow rescue. Group 2 received BMSYIX without immunosup-pressive therapy. The remaining groups received BMSPI'X and treatment on days 12 to 2S postrCCOnstitution with CyA at 25/mglkg per day (group 3). RAP at I mglkg per day (group 4). and FK 506 at I mglkg per day (group S). The follow-up was 60 days post-BMSYIX. Each group consisted of 7 to 10 animals. RESULTS Recovery From GVHD Acute GVHD was induced in recipients of allogeneic BMSPTX at a median day of 11 in the range of days 8 to 12. eyA, given at 2S mglkg per day aI\ddays 12 to 2S (group 3), was able to reverse GVHD in 55% of treated animals. The remaining rats failed to recover from GVHD and died during or after therapy. All animals (100%) receiving FK 506 at 1 mglkg per day on days 12 to 25 were rescued. [n contrast, treatment with RPM was ineffective in reversing GVHD. All animals died displaying signs of GVHD. Survival From GVHD Survival during and after immunosuppressive therapy is presented in Table 1. Irradiation controls receiving only TBI died within 16 days. Survival of RPM-treated rats (MST = 21.6 :t 5.0) wa.s similar' to that of untreated controls (MST = 22.1 :t 4.0). Survival of CyA-treated animals (MST = 29.2 :t 12.4) was prolonged compared to untreated controls (not statistically significant. P > .15). Only the FK 506-treated group (MST = 56.3 :t 4.1) A FI< 0 -.. + caA '1 ...... <> TEll 100 eo Ai ~ 60 Al > =-1 ~ 40 A .... #. 1000 TB OK '.0 20 0 • -.. • .0 I CaA 25 4- _ DAYS POST FeC06TIlUTlCN FIg 1. Survival from acute GVHD of allogeneic BMSP recipien1s treated with CyA, RPM, or FK 506. Anima.ls received either CyA at 25 mglkg per day (eyA 25), RPM at 1.0 mglkg per day (RPM 1.0), or FK 506 at 1.0 mglkg per day (FK 1.0) on days 12 to 25 post-BMSPTX. Included are untreated recipients of BMSP (untr 8M) and irradiation controls (1000 TBI). Data represents survival for 7 to 10 animals in each group. From the Depanment of Surgery, Division of Transplantation Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania: and the Department of Surgery, Heinrich Heine University of DOsseI-dorf, DQsseIdorf, Germany. Supported by Researctl Grant No. OK 29961 from the National InstitUtes of Health, Bethesda. Maryland, and the Veterans Admin-istration. Also supported by the Deutsche Forscl'lungsgemein-schaft. Address reprint requests to Thomas E. Starzl, MD. PhD, De-partment of Surgery, Division of Transplantation Surgery, Univer-sity of Pittsburgh, 3601 Fifth Avenue, Pittsburgh, PA 15213. il:) 1991 by Appleton & Lange 0041-1345191/$3.00/+0 3232 TransplantatiOn ProctIfIdings, Vol 23, No 6 (December), 1991: pp 3232-3233 , 1 1 1 I t ! i i i t i I i .-;, f~ I ~"K EFFECTS OF CvA. RAPAMYCIN. AND FK 506 showed significant prolongation of survival when com-pared to untreated controls (P < .01). DISCUSSION Cy A and FK 506 have been shown to be effective in reversing acute GVHD in 55% and 100%. respectively. of treated rats following allogeneic BMSPTX. In Cy A-treated rats. death during therapy was associated with the pres-ence of clinical signs of GVHD. In contrast. RAP was ineffective in reversing G VHD and rats died maintaining GVHD. Recurrence of GVHD after cessation of immuno-suppressive therapy was responsible for subsequent death of both Cy A and FK 506-treated animals. Both CyA and FK 506 have been reponed to interfere with the activation of T cells. Both drugs suppress the release of IL-2 and the expression of the IL.receptor .•. 5 RPM has little or no effect on these events. but inhibits the ---- response to IL·2.6 Why CyA and. in particular. FK 506 and not RPM. are effective in this model long after , ! ~ I -'" I: 3233 immunologic activation' starts. remains speculative and needs further investigation. Nevertheless. a similar effect of FK 506 has been shown in human organ transplantation where the drug was able to rescue patients experiencing rejection episodes of liver grafts despite prior treatment with CyA. OK'D. and corticosteroids. 7 REFERENCES I. Markus PM. Cai X. Ming W. el at: Surgery (in press) 2. Dceg HI. Slorn R. Thomas ED: Transplant Proc 15:1385. 1983 3. Santos G. Brookmeyer R. Sara! R. et at: Exp Hematology 13:427.1985 4. Kino T. Hatanaka H. Miyata S. et at: J Antibiot 40:1256. 1987 5. Tocci Ml. Matkovich DA. Collier KA. el at: J Immunol 143:718. 1989 6. Dumont Fl. Staruch MJ. Koprak SL. et at: J Immunol 144:251. 1990 7. Funl! Jl. Todo S. Tzakis A. et at: Transplant Proc (in press) 

The effect of cyclosporine, rapamycin and FK 506 the survival following allogeneic bone marrow transplantation

Name not available

Markus, P M

Cai, X

Selvaggi, G

Cooper, M

Harnaha, J

Fung, J J

Starzl, T E

University of Miami: Scholarship@Miami

http://d-scholarship.pitt.edu/4665/1/31735062118306.pdf

The effect of cyclosporine, rapamycin and FK 506 the survival following allogeneic bone marrow transplantation

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