Aitouche, A

Corry, R

Dodson, F

Egidi, F

Fontes, P

Fung, JJ

Gritsch, HA

Iyengar, A

Jordan, M

Pham, S

Rao, AS

Rastellini, C

Reyes, J

Shapiro, R

Starzl, TE

Zeevi, A

English

PubMed

Name not available

Augmentation of chimerism with perioperative donor bone marrow infusion in organ transplant recipients: A forty-four month follow-up

Rao, A. S.

Fontes, P.

Iyengar, A.

Shapiro, R.

Dodson, F.

Corry, R.

Pham, S.

Jordan, M.

Zeevi, A.

Rastellini, C.

Aitouche, A.

Gritsch, H. A.

Reyes, J.

Fung, J. J.

Starzl, T. E.

EGIDI, MARIA FRANCESCA

Archivio della Ricerca - Università di Pisa

Augmentation of chimerism with perioperative donor bone marrow infusion in organ transplant recipients: A 44 month follow-up

A.S. Rao

P. Fontes

A. Iyengar

R. Shapiro

F. Dodson

R. Corry

S. Pham

M. Jordan

A. Zeevi

C. Rastellini

A. Aitouche

F. Egidi

H.A. Gritsch

J. Reyes

J.J. Fung

T.E. Starzl

Crossref

Transplantation Proceedings

Rao, A. S

Fontes, P

Aitouche, A

Egidi, F

Gritsch, H. A

Reyes, J

Fung, J. J

Starzl, T. E

Iyengar, A

Shapiro, R

Dodson, F

Corry, R

Pham, S

Jordan, M

Zeevi, A

Rastellini, C

University of Miami: Scholarship@Miami

Augmentation of chimerism with perioperative donor bone marrow infusion in organ transplant recipients : A 44 month follow-up

D-Scholarship@Pitt

ELSEVIER Augmentation of Chimerism With Peri operative Donor Bone Marrow Infusion in Organ Transplant Recipients: A 44 Month Follow-Up A.S. Rao, P. Fontes, A. Iyengar, R. Shapiro, F. Dodson, R. Corry, S. Pham, M. Jordan, A. Zeevi, C. Rastellini, A. Aitouche, F. Egidi, H.A. Gritsch, J. Reyes, J.J. Fung, and T.E. Starzl '"I IE HAVE previo~y documented the long-term per-V V sistence of donor cell chimerism after successful organ transplantation (Tx) and have postulated that it plays a seminal role in allograft acceptance and in the induction and perpetration of donor-specific tolerance.1•2 To further enhance the salutary effects of chimerism we have aug-mented this phenomenon, since December 1992, by infus-ing unmodified donor bone marrow (BM) into 190 organ allograft recipients; the unavailability of consent to retrieve vertebral bodies has resulted in accrual of 110 contempo-raneous controls. We present here an interim analysis of these patients at their most recent follow up. MATERIALS AND METHODS Patients Since December 1992. 183 patients have simultaneously received transplants of ABO compatible donor BM and liver (n = 54). kidney (n = 35). kidney + pancreas (n = 32). kidney + islets (n = 7). heart (n = 21). lungs (n = 18). small bowel (n = 13) and multi·organ (n = 3). Additionally. since the initiation of a modified protocol in April 1996. 7 (liver n = 3. kidney n = 3. kidney + delayed islets n = 1) allograft recipients have received multiple infusions of donor BM consecutively from days 0 to 4 post Tx. The mean follow up was 498 =: 326 days and the mean recipient and donor ages were 42 =: 15 and 30 =: 15 years respectively. Further-more. 110 (liver n = 31, kidney n = 40. heart n = 21. lungs n = 10. small bowel n = 7 and multi-organ n = I) allograft recipients for whom donor BM was unavailable were monitored as controls. Their mean follow up was 552 =: 325 days and mean recipient and donor ages were 45 =: 15 and 33 =: 18 years respectively. The outcome in BM augmented (n = 8) and non-augmented (n = 2) kidney + islet recipients is detailed elsewhere in this issue (see Rastellini. et al). BM Isolation Cells from the wrtebral bodies of cadaveric donors were isolated by a method described previously. J In patients receiving a single perioperative dose following organ revascularization. 3 to 5 x 10" unmodified cells/kg body weight were infused via a central intra-venous line. In those who received multiple inocula of donor BM. I x 10' cells/kg body weight/d were infused consecutively from days Il to 4 post Tx. The BM cells used in the latter protocol were maintained in culture and not cryopreserved prior to Infusion. 0041-1315/971$17.00 PII S0041-1345(96)00536-2 1184 Immunosuppression (IS) The recipients were not subjected to any cytoablative or cytoreduc-tive conditioning regimen prior to organ Tx and were maintained on routine IS which included tacrolimus and steroids. Minor adjustments in the doses of routine IS were made to treat all episodes of rejection. Only when steroid-resistant rejection was encountered was therapy with a short course of OKT3 or ATG deemed necessary. In Vitro Studies The immune status of the recipient was monitored serially by mixed leukocyte reaction. limiting dilution assay. proliferation against recall antigens. ConA and PHA; the methodology for which has been reported previous/y.4 The results of these assays are reported elsewhere in this issue (see Zeevi. et all. For qualitative assessment of chimerism. recipients' PBMC were used in which the presence of donor cells was detected by cytoftuorography and PCR. Serial quantitative evaluations of donor cell chimerism in a selected cohort of study and control patients was performed using a modified limiting dilution PCR assay. the details of which are reported elsewhere.5•6 The multilineage character of chimerism was also ascertained by PCR detection of donor DNA in lineage + cells sorted from recipients' PBMC. The evidence for the presence of donor dendritic cell progenitors and therefore of engraftment was obtained by propagation of recipients' PBMC in rhGM-CSF and rhIL-4-enriched cultures using a protocol described previous-ly. 7 Subsequent to enrichment for lineagenUII!MHC class II + pop-ulation. the presence of donor DNA within the sorted cells was confirmed by PCR analysis. RESULTS AND DISCUSSION The adjuvant 8M infusion was safe and no complications uniquely ascribed to this procedure were witnessed in any of From the Thomas E. Starzl Transplantation Institute and the Departments of Surgery (A.S.R.. P.F .• A.I.. R.S .• F.D .• R.C .• S.P .• M.J .• C.R.. J.R.. J.J.F .. T.E.S.) and Pathology (A.S.R.. A.Z.). University of Pittsburgh Medical Center. Pittsburgh. Pennsylva-nia. Aided by Project Grant No. AI 40329 and OK 29961 from the National Institute of Health. Bethesda. Maryland. Address reprint requests to A.S. Rao. MD. DPhil. Thomas E. Starzl Transplantation Institute. E1545 Biomedical Science Tower. 200 Lothrop Street. Pittsburgh. PA. 15213. © 1997 by ElseVier Science Inc. 655 Avenue of the Americas. New York. NY 10010 Transp/anratlon PrOCeedings. 29. 1184-1185 (1997) , 4 I I ,-,,: AUGMENTATION OF CHIMERISM 1185 Table 1. Graft Function and Percent of BM-Augmented and Nonaugmented Organ Recipients Who Are Off Steroids and Are at Least 12 Months Posttransplantation Graft Function (X :;: SO) Organs Tx Uver Study Control Kidney Study Control Heart Study Control Lung Study Control n 34 26 45 27 10 9 6 7 TBili rng/dL 0.5:!: 0.3 0.3:t 0.2 Creatinine mg/dL 1.5 :t 0.5 2.0 :t 0.9 the 190 organ allograft recipients. All but 17 of 190 (9%) BM augmented patients are alive as compared to 131110 (12%) control recipients. who have died during the course of this follow up. It is noteworthy that no deaths in the augmented group were related to BM infusion. Addition-ally, grafts in nine (kidney n = 4, kidney + pancreas n = 1. pancreas n = 4) study patients were lost to causes unrelated to BM infusion. Similarly grafts in five (kidney n = 1. kidney + pancreas n = 1. pancreas n = 3) control patients were lost during the course of this follow up. No evidence of any complications was witnessed in any of the seven pa-tients who had received multiple BM infusions during the course of their follow-up (19-114 d). All of the surviving patients have adequate graft function (Table 1). The tempo. severity and cumulative incidencc of rejec-tion was comparable E~SM%F in the patients in the study and control group. Graft versus host disease was only witnessed in 2 (1 %) BM augmented recipients (both of liver) whose outcome has been reported previously.J In patients who are at least 12 months post Tx. a steroid-free existence has been achieved in 61 % study and 46% control patients. Interestingly. a statistically higher percentage of kidney allograft recipients in the study group (71 %) are off steroids as compared to that to controls (48%: Table 1). No patient is completely off IS. Having previously reponed that the incidence of chimer-ism is much highcr in the study than in the control group;1.,) we embarked on developing an assay for its serial quanti-tative assessment in a selected cohort of study and control patients. Using LOA-peR assay. the levels of chimerism were found to be at lcast I () to 100 fold higher in BM augmented reCipients at up to 2 to J years post-Tx, The augmented levels of chimerism in the PBMC uf studv patients were indeed ot multilin.:ag.: charact.:r tor the Cardiac Output (Urnin) 4.9:t 0.9 5.0:t 1.2 FEY, (Ll 1.8:t 0.5 1.9 :t 0.9 011 Steroids (%l 23/34 (68) 18126 (54) 32/45 (71) 13127 (48) 2110 (20) 119(11) 1/6 (16.67) Ofl(O) presence of donor DNA by PCR was confirmed in sorted T (CDr), B (CD14+) and NK (CDS6+) cells. Unequivocal evidence for BM engraftment was obtained when the presence of donor DNA was confirmed within the lin-eagenull/class II+ cells enriched from colonies harvested from cytokine-rich cultures which allows for selective prop-agation of dendritic cell progenitors. Taken together these data suggest that single and multi-ple perioperative infusion of BM is safe and is associated with augmentation of chimerism. Although a higher inci-dence of steroid-free existence was witnessed in study as compared to control patients. it is too early to speculate if this observed outcome would sustain itself in a longer follow up. It is indeed interesting to note that the salutary effects of augmented chimerism on the incidence of evolve-ment of chronic rejection are already discernible in lung transplant recipients for 2 of 7 (29%) surviving control patients have evidence for the development of obliterative bronchiolitis. a complication yet not witnessed in the study population who have a comparable duration of follow up. REFERENCES 1. Starzl TE. Dcmetris N. Murasc N. ct al: Lancet 339:1579. 1992 :!. Starzl TE. Dcmelris N. Trucw M. et al: Hcpalolugy 17: 11:!7. 1993 3. Fontes P. Rao AS. D.::mctris N. ct ai: Lancet 344:151. l'N4 4. Zeevi A. Pavlick M. Lombardozzi S. ct al: Transplantation 59:616. 1l)Y4 5. Taswell C: J Immunol 1:!6:1614. IYSI 6, Billadcau D. Quam L. Thomas W. Cl al: Blood SO:lHIS. 1992 7, Romani N. Gruner D. Srang E. ct al: J Exp Mcd IHO:H3. 1')<)4 X. Ruo AS. FOlltes P. Z.:evi A. ct al: Transplant Proc 27:210. 1<)<)5 

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Augmentation of chimerism with perioperative donor bone marrow infusion in organ transplant recipients: A 44 month follow-up

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