Ball, Edward D

Demetris, Anthony J

Fontes, Paulo AC

Nalesnik, Michael A

Ricordi, Camillo

Rybka, Witold B

Starzl, Thomas E

Tzakis, Andreas G

Ukah, Ferdinand O

Zeevi, Adriana

PubMed

Ricordi, C

Tzakis, AG

Demetris, AJ

Zeevi, A

Rybka, WB

Nalesnik, MA

Ukah, FO

Fontes, PAC

Ball, ED

Starzl, TE

Name not available

Reversal of graft-versus-host disease with infusion of stored autologous bone marrow cells following combined liver-bone marrow allotransplantation in man

D-Scholarship@Pitt

Reprinted from TRANSPLANTATION SClRNCl! Vol 3. No. I, April 1993. Copyright, e 1993, by R. G. Landes Company. Printed in U.s.A. Reversal of Graft-Versus-Host Disease with Infusion of Stored Autologous Bone Marrow Cells Following Combined Liver-Bone Marrow Allotransplantation in Man CAMILLO RICORDI, ANDREAS G. TZAKIs, ANTHONY J. DEMETRIS,ADRlANA ZEEVI, Wrrow B. RYBKA, MICHAEL A. NALESNIK, FERDINAND O. UKAl-I, PAULO A.c. FONTES, EDWARD D. BALL AND THOMAS E. STARZL * Pittsburgh Graft-versus-host reaction was first described following splenocyte transplantationl and was correctly attributed to recog-nition of the host by immunologically competent cells of the graft. Soon, the same phenomenon was recognized in recipients of organs that are rich in lymphoid tissue2 and was demonstrated after parent to offspring Fl hybrid intestinal transplantation in rats. 3 An increas-ing frequency of graft-versus-host-disease (GVHD) has been ob-served after transplantation of other organs, including the hu-man liver4 . l2 In this report, we describe reversal of GVHD in a recipient of a combined liver-bone marrow transplant by infusion of stored autologous bone marrow cells. GaseReport A 56-year-old man with a gastric leiomyosarcoma with liver metastases underwent upper abdominal exenteration and orthotopic liver allotransplantation on July 16, 1992. Shortly before operation, the patient was treated with a single dose of 550 rads thoraco-abdominal lymphoid irradiation (Til). Immediately after opera-tion, 19 x 109 donor bone marrow cells harvested from 10 vertebral bodies were infused IV through a central line. Postoperative immunosuppression was with FK 506 and prednisone. A skin rash developed within the first postoperative week. The rash, that was initially mild and confined to the areas exposed to the preoperative Til, progressively worsened and the diagnosis of GVHD was made on a skin biopsy 15 days following surgery. Histologic examination of the skin biopsy revealed a mild, pre-dominantly T lymphocyte infiltrate localized to the upper dermis that was associated with focal exocytosis and spongiosis and with occasional kerarinocyte necrosis. The infiltrating cells were recog-nized as of donor HLA type by immunostaining. A second biopsy on postoperative day 21 revealed more florid changes that included acantholysis and focal cleft formation. A third biopsy one week later showed continued damage to keratinocytes and adnexal cells, with an inflammatory infiltrate of the upper dermis that was signifl-*Correspondence address: The Transplanration Instirme, UniversiryofPirtsburgh, 5C Falk Clinic, 3601 Fifth Avenue, Pirtsbnrgh, PA 15213. cantly more conspicuous than in prior biopsies. Immunoperoxidase stains showed the cells to be T lymphocytes of donor origin. The skin involvement spread to more than 80% of the body surface, including the palms, soles and face. The progression of GVHD was not altered by increases or decreases of FK 506 or prednisone. Throughout this time, 22 to 34% of the circulating lymphocytes were donor phenotype, as determined by flow cyrometry using appropriate anti-HLA class I monoclonal antibodies. On the 42nd and 43rd posroperative days, 2.83 X 108 autolo-gous bone marrow cells/kilograms were infused. The skin rash promptly improved and completely resolved within two weeks after the autologous cell infusion with a reduction of circulating donor lymphocytes which never again exceeded 10% of the total and was in the 3% range on postoperative day 96. The patient who had been gravely ill was restored to a sense of well being and was discharged three weeks following the autologous bone marrow infusion. Donor-specific alloreactivity was assessed in mixed lymphocyte reaction (MLR) and in cell-mediated lympholysis (CML) pretransplant, during the first month postsurgery and following autologous bone marrow infusion. Prerransplant recipient periph-eral blood exhibited proliferative responses to donor or third party irradiated spleen cells. During the first postoperative month, his MLR responses to both donor and third party were significantly suppressed. However, following infusion of the autologous mar-row the MLR responses were reestablished, and the patient showed donor-specific CML activity. Restoration of immuno-competence towards the donor coincided with the clinical reso-lution of the GVHD. Cotnment GVHD in intestinal or hepatic recipients cannot be defined by conventional criteria because the donor origin of the transplanted organs prevents them from becoming a target of GVHD while exposing them to the risk of rejection. Consequently, the most unequivocal finding may be a skin rash such as that observed in approximately 5% of our liver allograft recipients. For years, these dermatologic manifestations were attributed to a drug or to an allergic reaction, until it was realized that systemic chimerism occurs after all successful transplamations, creating the possibility ofGVHD in every case.' 2 Storage of autologous bone marrow could represent a safety net in pilot trials of bone marrow-organ transplantation, until the risk for severe GVHD is better understood or until alternative ap-proaches are developed to prevent GVHD, such as a bone marrow component approach, or by UVB irradiation of the allogeneic bone marrow (Mark Hardy, this issue). Understanding the difference between the autologous naive cells that had been in storage and the immunocytes in the patient that had become defenseless against attack by cohabitation for six weeks with donor cells would go far in explaining the changes brought about by chimerism. The therapeuric rescue was reminiscent of a tolerance breaking experiment mentioned in the classic article of Billingham, Brent, and Medawar. I3 However, the incompleteness of the effect in our patient allowed control of the GVHD without rejection of the liver allograft. REFERENCES 1. Billingham R, Beem L. Quantitative studies on transplamation immunity. IV. Induction of tolerance in newborn mice and studies on the phenomenon of rum disease. Philos Trans R Soc Lond (Bioi) 1956; 242:439-477. 2. Starzl TE, Kaupp HA)r, Brock DR, et a!. Homotransplamation of multiple visceral organs. Am] Surg 1962; 103:219-229. 3. Monchik G), Russell PS. Transplamation of the small bowel in the rat: technical and immunologic considerations. Surgery 1971; 70:693-702. 4. Ramsey G, Nushacher], Scatzl TE, Lindsay GD. Isohemagglutinins of graft origin after ABO-unmatched liver transplantation. New Engl) Med 1984; 311:1167-1170. 5. Burdick)F, Vogelsang GB, Smith W) et a!. Severe graft-versus-host disease in a liver rransplam recipiem. New Engl) Med 1988; 319:689-691. 6. Marubayashi S, Matsuzaka C, Takeda A et a1. Fatal generalized acute graft-versus-host disease in a liver transplam recipiem. Transplamation 1990; 50:709-71l. 7. Bhaduri BR, Tan KC, Humphreys S et a!. Graft-versus-host disease after orthotopic liver transplantation in achild. Transplam Proc 1990; 22:2378-2380. 8. Roberrs)P, Ascher NI., Lake) et a!. Graft vs. host disease after liver trans plamation in humans: a report offour cases. Hepatology 1991; 14:274-281. 9. Jamieson NV,)oysey V, Friend PJ et a!. Graft-versus-hoS[ disease in solid organ transplamation. Transplant Int 1991; 4:67-71. 10. Rosen CB, Moore SB, Barrs KP et a!. Clinical and pathological fearures of graft-versus-bost disease after liver transplantation: A case report and review of the literature. Clin Transplantation (In Press). 11. Comenzo RI., Malachowski ME, Rohrer RJ et a!. Anomalous ABO pheno-type in a child after an ABO-incompatible liver transplantation. New Eng ) Med 1992; 326:867-89,. 12. Starzl TE, Demetris A), Trucco M et al. Cell Migration and Chimerism Mter Whole Organ Transplantation: The Basis Of Graft acceptance. Hepatology (In Press). 13. Billingham R, Brent L, Medawar P. Quantitative studies on tissue trans-plantation immunity. III. Actively acquired tolerance. Philos Trans R Soc Lond (BioI) 1956; 239:357-412. 

Reversal of Graft-Versus-Host Disease with Infusion of Stored Autologous Bone Marrow Cells Following Combined Liver-Bone Marrow Allotransplantation in Man.

Ricordi, Camillo

Tzakis, Andreas G

Demetris, Anthony J

Zeevi, Adriana

Rybka, Witold B

Nalesnik, Michael A

Ukah, Ferdinand O

Fontes, Paulo A C

Ball, Edward D

Starzl, Thomas E

University of Miami: Scholarship Miami

Reversal of Graft-Versus-Host Disease with Infusion of Stored Autologous Bone Marrow Cells Following Combined Liver-Bone Marrow Allotransplantation in Man

http://d-scholarship.pitt.edu/4913/1/31735062113208.pdf

Reversal of Graft-Versus-Host Disease with Infusion of Stored Autologous Bone Marrow Cells Following Combined Liver-Bone Marrow Allotransplantation in Man.

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