Demetris, AJ

Fujisaki, S

Murase, N

Qing, Y

Starzl, TE

Tanabe, M

Todo, S

English

PubMed

Name not available

Bone marrow augmentation for heart, liver, and small bowel transplantation: prolongation of graft survival and incidence of graft-versus-host disease

D-Scholarship@Pitt

Bone Marrow Augmentation for Heart, Liver, and Small Bowel Transplantation: Prolongation of Graft Survival and Incidence of Graft-Versus-Host Disease \/\ \\. D N. Murase, A.J. Demetns, s. Fujlsakl, M. Tanabe, Y. Qmg, S. Todo, and T.E. Starzi ( THE persistence of donor leukocvtes in recipients after transplantation (chimerism) has been postulated as the basis for graft acceptance. I.: There have been direct efforts to augment chimerism in order to increase the chance of graft acceptance. even though the mechanism of the bidirectional modulation between host and chimeric cells to achieve donor-specific hyporeactivity is not clear. In this study we examined the influence of donor bone marrow infusion at the time of solid organ transplantation on the levels of chimerism and the outcome of transplants. MATERIALS AND METHODS ACI (RTI") and Lewis (LEW. RTII) rats (Harlan Spragut:·Daw!ev. Indianapolis. Ind.) were used as donors and recipients. rcspec-lIvclv. Orthotopic small bowel. livcr. and heterotopIc abdominal heart transplants were performed using the methods previously dcscnbed J ·4 Intramuscular FK 500 (Fujisawa Pharmaceutical Co. Ltd .. Osaka. Japan) was used at a daily dose of 1 mg/kg on days O. J. and 2. Bonc marrow cells werc obtained from tibias and femurs of naive ACI rats and 250 x 10" cells were infused to each recipient on the day of solid organ grafting. Whole organ graft survival and the incidence of graft·versus-host disease (GYHD) were examined With or without simultaneous bone marrow infusion. The percent-ages of donor phenotvpe lymphocytcs In the recipient blood were analyzed by 110w cytometry uSing MAb specific for donor (ACI) major histocompatibility complex (MHC) class I (MN4-<J I-n. Sero-ICC. UK). RESULTS :Y1edian heart graft survival of animals treated with a J-day course of FK 5(1) alone was 4~ days (n = h). The addition or donor bone marrow infusion on the day of heart grafting significantly (P < .(1) improved graft survival. and all ~mimals survived more than 100 days (n = h). FK 506 treatment alone prolonged small bowel graft survival to a median of 57.5 days (n = 6). These animals died exclusively of rejection without signs of GVHD. Interestingly. 5 of H animals developed GVHD (skin rash) between 20 and 35 days after the simultaneous small bowel and bone marrow transplantation. GVHD was fatal in 4 of 5 :mimals and death occurred between 25 and 43 davs. One animal recovered from GVHD and survived for 200 days. at which time histopathological evidence of chronic rejection was noticed. The remaining 3 animals in this group were free trom GVHD: however. rejection was the primary cause 01 animal death between 41 and 51 days after grafting. Finally. a median small bowel graft survival of 42 days with bone marrow infusion was slightlY shorter than that without bone marrow infusion. All FK 506 treated recipients of liver 174 grafts lived more than 100 days regardless of bone marrO\\ infusion. When the liver and bone marrow were trans-planted together. 2 of 5 recipients showed temporary GVHD. which spontaneously resolved. Flow cytometric analysis revealed that bone marrow infusion increased the numbers of donor cells in the recip-ient circulation. when compared with those after solid organ transplantation alone. Detection of donor cells by flow cytometry was difficult in recipients of heart grafts but relatively easy after liver transplantation. After small bowel grafting, especially with bone marrow infusion. donor cells remained in the recipients for a long time. They rapidly increased to 20S"r to hO'!/: in GYHD animals. but were not detected after recoverv from GVHD. DISCUSSION The engraftment of allogeneic cells with a state of donor-specific tolerance has been achieved in cytoablated recipi-ents of bone marrow transplantation.5 Consequently. the strategic use of donor bone marrow to establish acquired transplantation tolerance was commonly applied in combi-nation with ALG. h As seen in this studv and in the results of a clinical trial. 7 bone marrow cell inf~sion along with solid organ transplantation affected the graft outcome through the engraftment of bone marrow cells under conyentional immunosuppression. The graft that profits most from this procedure may be the organ. which has relatively poorly distributed passenger lymphocytes. since the best result was obtained in the heart graft in this study. Development of GVHD in small howel plus bone mar-row recipients suggests that the quality. as well as the quantity. of whole donor inoculum afiects the subsequent host-graft relationship. Further strategies tll improve graft survival may be necessary. REFERENCES I. Starzl TE. Dcmetris AJ. Murase N. CI al: Lancet 339: 1579. 1992 2. Starzl TE. Dcmetris AJ. ~1urasc N. CI al: Immunol Today 14:326. 1l)<J3 From Pittsburgh Transplant Institute, Departments of Surgery and Pathology, University of Pittsburgh. Pittsburgh, Pennsylva-nia. Address repnnt requests to Nonko Murase, Pittsburgh Trans-plantation Institute. 4C Falk CliniC. 3601 Fifth Ave. PittSburgh, PA 15213. !') 1995 by Appleton & Lange 0041-1345/95/$3.001 +0 Transplantation Proceedings, Vol 27. No 1 (February). 1995: pp 174-175 '-", ~-K V .\' 1-d ly Jt el lIs Ily ot OT-pi-the red lbi-s of olid ugh mal this lorly was mar-the luent graft ':1579, Today )urgery 'lsylva-Trans-rgh, PA ~c , --" '" ~D:;: " 'i ~jK ';' '-." t, ~ D~~ ~K I ',,: .. ! :.; 'i'; ':;Jo t "-'" l."_ ~ GRAFT-VERSUS-HOST DISEASE 3, Ono K. Lindsey ES: J Thorac Cardiovasc Surg 7:2:!5. 1%1) .j, Murase N. Demelris AJ. Kim DG. et al: Surgery 108:880. 19Q(1 5. Main JM. Prehn RT: J Natl Cancer lnst 15:1023. 1955 175 h. Monaco AP. Wood ML. Russell PS: Ann NY Acad Sci 129:190.1966 7. Fontes P. Rao AS. Demetris AJ. et al: Lancet 344: 15 1. IIJl).j 

Bone marrow augmentation for heart, liver, and small bowel transplantation: Prolongation of graft survival and incidence of graft- versus-host disease

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Bone marrow augmentation for heart, liver, and small bowel transplantation: Prolongation of graft survival and incidence of graft- versus-host disease

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