Aitouche, A

Corry, R

Demetris, AJ

Dodson, F

Fontes, P

Fung, JJ

Jordan, M

Rao, AS

Rastellini, C

Rilo, HLR

Rosner, G

Rugeles, M

Shapiro, R

Starzl, TE

Trucco, M

Zeevi, A

English

PubMed

D-Scholarship@Pitt

-----_._----Enhancement of Donor Cell Chimerism in Whole Organ Allograft Recipients by Adjuvant Bone Marrow Transplantation AS. Rao, P. Fontes, A Zeevi, M. Rugeles, R. Shapiro, M. Jordan, R. Corry, F. Dodson, H.L.R. Rilo, C. Rasteliini, A. Aitouche, G. Rosner, M. Trucco, AJ. Demetris, J.J. Fung, and T.E. Starzl THE ADVENT of novel immunosuppressive agents has made successful transplantation of organ allografts a clinical reality. However, chronic use of these nonspecific drugs is associated with unwanted side effects; necessitating the evolution of strategies that would allow for the induc-tion of donor-specific tolerance, enhancing allograft sur-vival and ultimately leading to reduction or withdrawal of immunosuppression (IS). Having speculated that persis-tence of donor cell chimerism may play an important role in the, acceptance of whole organ allografts,I-3 we initiated a prospective trial in December 1992 to enhance this phe-nomenon by adjuvant infusion of unmodified bone marrow (BM) into 85 recipients of primary whole organ allografts. Failure to obtain permission to harvest vertebral bodies from the cadaveric donors resulted in accrual of 54 recipi-ents of organ alone, which were followed as contempora-neous controls. Reported herein is the outcome of these patients at their latest follow-up. MATERIALS AND METHODS Patients Between December 1992 and December 1994. 85 patients were simultaneously transplanted with ABO-compatible unmodified do-nor BM and liver (II = 34). kidney (n = 36). heart (n = 10), or lung (n = 5). The mean follow-up was 360:: 179 (range, 90 to 852 days). The mean recipient age was 46 :: 11.3 years. and the mean donor age was 32.7 :: 16.2 years. Additionally. there were 54 recipients of liver (n = 29). kidney (n = 20). heart (1/ = 4). or lung (1/ = I) allografts alonc nn whom consent to harvest vertebral bodies from the cadaveric donors was not available were monitored as con-trols). Their follow-up ranges from 130 to 535 days (405 :: 107 days). Isolated pancreatic islets wen: infused into one lil'er and six kidney rccipients who also received adjuvant BM. Seven 8M-augmented and three nonaugmcnted kidney recipients also re-ct:ived a concomitant pancreas transplant. Bone Marrow and Pancreatic Islets Cell Isolation 1,\1 cells werc isobted from the wrtcbral bodies of the cadaveric dOllllrs by a method d~scribed previousl\': Following organ rc\as-cularization. :; to .'i )( 10' unmodified cells.kg body weight were infused via a central IV line into the recipients. Iskts from the panen:ata of the B\1'organ donor were isolateu by a modification of the autllmated methlld.' and subsequently infused into the portal vein ()f the allu~raft recipients shortly after fI.'vascularization. Immunosuppression All patients rel'cl\cd tacrolimus along with ,kroids and did not undn~ll ;iI1Y evwablative or cytllreductlve conditioning priLlr to organ transpLlIllation. All epislldes of rejectinn or graft-versus-host dl,case (Ci VII D) were treated with min()r moditicatiuns in doses of routine IS. In the event a steroid-resistant rejection was encoun-tered, it was treated with a short course of OKTI or ATG. In Vitro Studies Pretransplant and serially posttransplant (every other month) in vitro studies were performed using the PBMCs of the recipients to detect chimerism (by flow cytometry and PCR) and to determine their immune status (by MLR, LOA, recall antigens, ConA, and PHA). These methods have been detailed elsewhere.' RESULTS AND DISCUSSION No complications of BM infusion were witnessed in any of the 85 primary organ allograft recipients, and their conva-lescence was rapid. All but four (5%) BM-augmented recipients are alive whereas, 7 of 54 (13%) control patients died during this follow-up (Table 1). None of the deaths in the augmented group were related to BM infusion. The two BM-augmented liver patients succumbed to fulminant sep-ticemia 3 and 5 weeks posttransplantation_ Two additional heart and BM recipients died with functioning grafts on postoperative days 24 and 267 due to septicemia and pulmonary thrombo-embolism, respectively. Two kidney allografts in the BM-augmented group were lost 16 months posttransplantation (noncompliance in one and rejection in the other). Polyoma virus infection and rejection was the cause for loss of another kidney approximately 375 days posttransplantation. The tempo, severity, and incidence of rejection were comparable in the patients in the study and control group. Only two (2.3%), both BM-augmented liver recipients, developed asymptomatic GVHD. Limited to the skin, it resolved spontaneously in one. whereas a slight increase in routine steroid dose was required for its invo-lution in the other.4 The most recent blood sample obtained from evaluable patients showed a significantly higher inci-dence (69 of 79.87%) of multilineage donor cell chimerism in the 8M-augmented as compared to that in the control (23 to 43, RP~DcF group (Table 1). Additionally. 52':, of the From the Pittsburgh Transplantation Institute and the Depart-ments of Surgery (AS.R_, P.F., M.A., A.S., M.J., R.C., F.D., H.L.R.R., C.R., AA.J.J.F., T.E.S.), and Pathology (AS.R., AZ., A.J.D.) and Pediatrics (G.R., M.T.) University of Pittsburgh Med-Ical Center, Pittsburgh, Pennsylvania. Aided by Project Grant No. DK 29961 from the National Institute of Health, Bethesda. Maryland. Address reprints to Abdul S. Rao. MD, DPhil, Pittsburgh Transplantation Institute, E1545 Biomedical Science Tower. 200 Lothrop Street, Pittsburgh, PA 15213. I~ 1995 by Appleton & Lange 0041-1345/95/$3.00/+0 Transplantation Proceedmgs, Vol 27, No 6 (December), 1995: pp 3387-3388 3387 I ! 3388 RAO. FONTES. ZEEVI ET AL Table 1. Current Graft Function, Survival, and Donor Cell Chimerism in BM-Augmented and Nonaugmented Whole Organ Allograft Recipients Graft survival Transplant groups n n (%) Livers: 8M-Augmented 34 32/34 (94%) Nonaugmented 29 25/29 (86%) Kidney: 8M-Augmented 36 33/36 (92%) Nonaugmented 20 17/20 (85%) Hearts: 8M-Augmented 10 8/10 (80%) Nonaugmented 04 4/04 (100%) Lungs: 8M-Augmented 05 5/05 (100%) Nonaugmented 01 0 (0%) 'In evaluable patients at the last sample tested. 8M-augmented liver recipients had evidence of donor-specific hyporeactivity as compared to 26% of the controls. It is noteworthy that in the recipients of other organs. immune modulation was analogous in both the control and the study group at the last sample tested. In summary, adjuvant 8M infusion into whole organ allograft recipients was safe and associated with augmenta-tion of chimerism. Although its eventual effect remains speCUlative, it could be argued that its presence may have salutary effects on graft and patient survival and may also reduce the risk of chronic rejection.6 Graft function (y - SD! Positive for donor cells' T. Bill (mgldL) Creatinine (mg/dL! n (%) 0.6:': 2 30/31 (97%) 0.7:,: 3 13/25 (52%) 1.9 :': 1.2 30131 (97%) 2.1 :!: 1.3 09114 (64%) Good graft function 5/8 (63%) Good graft function 3/4 (25%) Good graft function 4/5 (80%) REFERENCES 1. Starzl TE. Dcmctris AJ. Murase N. et al: Lancet 339:1579. 1992 2. Starzl TE. Demctris AJ. Trucco M. ct al: Hepatology 17: 1127, 1993 3. Starzl TE. Dcmetris AJ: JAMA 273:876. 1995 4. Fontes P. Rao AS. Dcmetris AI, et al: Lancet 344: 151. 1994 5. Ricordi C. Lacy PE. Finke HI: Diabetes 37:413. 1988 6. Murase N. Starzl TE. Tanabe M. et al: Transplantation 60: 158. 1995 .--

Enhancement of donor cell chimerism in whole organ allograft recipients by adjuvant bone marrow transplantation

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Enhancement of donor cell chimerism in whole organ allograft recipients by adjuvant bone marrow transplantation

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