Banas, R

Bentlejewski, C

Corry, R

Dodson, F

Egidi, F

Fontes, P

Fung, JJ

Griffith, B

Iyengar, A

Jordan, M

Keenan, R

Pavlick, M

Pham, S

Rao, AS

Shapiro, R

Spichty, K

Starzl, TE

Zeevi, A

English

PubMed

D-Scholarship@Pitt

I I I I , ., ELSEVIER Three Years of Follow-Up of Bone Marrow-Augmented Organ Transplant Recipients: The Impact on Donor-Specific Immune Modulation A. Zeevi, M. Pavlick, R. Banas, C. Bentlejewski, K. Spichty, A.S. Rao, P. Fontes, A. Iyengar, R. Shapiro, F. Dodson, M. Jordan, S. Pham, R. Keenan, B. Griffith, R. Corry, F. Egidi, J.J. Fung, and T.E. Starzl THE DISCOVERY of the presence of previously unsus-pected microchimerism in successful long-term liver and kidney transplant recipients prompted us to postulate that these cells are essential for graft acceptance and the induction of donor-specific hyporeactivity.t-3 This observa-tion provided the basis for the initiation of a new therapeu-tic strategy which involved infusion of donor bone marrow (BM) cells under conventional immunosuppressive treatment with tacrolimus and prednisolone:~ The initial outcome of sequential in vitro immunologic evaluations performed to determine the development of donor-specific hyporeactivity in the first 15 BM-augmented and 16 contemporaneous controls has been described previously.5.6 We report here the immune profile of 102 BM-augmented and 57 control patients who were at least 6 months posttransplantation. MATERIALS AND METHODS Case Material Since December 1992. 138 study patients have received simulta-neous BM + whole organ transplants. Ninety-two recipients of whole organs for whom permission could not be obtained for BM procurement from cadaveric donors were monitored as controls. Sequential immune monitoring was possible in 102 study (liver n = 31. kidneys n = 27. kidney + pancreas n = 19. kidney + islets n = 6. heart n = 10. lung n = 8) and 57 control (liver n = 23. kidney n = 10. kidney + pancreas n = 7. kidney + islets n = 2. heart n = 9. and lung n = 6) patients who were at least 180 days posttransplantation and for whom donor cells were available. Immunosuppression was similar in both groups and consisted of tacrolimus and prednisolone.· All patients were analyzed for donor chimerism by FACS andlor polymerase chain reaction (PCR) using HlA-specific markers.· In Vitro Immune Responsiveness Pre- and serially posttransplant (5, 4. and 3 times in 1st. 2nd and 3rd year respectively) monitoring of recipient's immune status was carried out by evaluating the proliferative responses of the periph-eral blood mononuclear cells (PBMC) to mitogens (conconavalin A [ConAl. phytohemagglutinin [PHA)). to recall antigens (tetanus toxoid). and to mixed lymphocyte reaction (MLR) with donor and third-party cells. The details of the assays were summarized elsewhere.h.7 The criteria developed to serially evaluate in vitro immune status were also published previously.b.7 Briefly. we have classified the transplant recipients based on their in vitro respon-siveness as either donor-specific hyporeactive. donor-specific inter-mediate. reactive. or suppressed. RESULTS AND DISCUSSION In transplant recipients who were augmented with BM, with the exception of those receiving hearts, progressive donor-From the Thomas E. Starzl Pittsburgh Transplantation Insti-tute, and the Departments of Pathology and Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Supported by project grant OK 29961 from the National Institutes of Health, Bethesda, Maryland, and the Pathology, Education, and Research Fund. Address reprint requests to Adriana Zeevi, PhD, Department of Pathology, Biomedical Science Tower, Room W1551, Univer-sity of Pittsburgh, Pittsburgh, PA 15261. Table 1. Results of MLR in 8M-Augmented Organ Transplant Recipients and Its Correlation With Incidence of Chimerism DSHI No. No. %011 Chimerism Type of Transplant Transplants (%) POD:!: SO Steroids (%) Uver" 29 15 (48) 872:!: 199 87 86 Kldneyt 23 10 (43) 605:!:214 50 78 Kidney + pancreas 19 8 (47) 482 :!: 151 50 86 Kidney + islet 6 4 (67) 891 :!: 148 75 75 Heart 10 2 (20) 824:!: 20 NA 50 Lung 8 5 (62) 587 :!: 190 NA 80 -Two recIpients were suppressed (nonresponsive to both donor and third-party stimulators). TFour organs were lost In pallents who were reactive. © 1997 by Elsevier Science Inc. 655 Avenue of the Americas, New York. NY 10010 Transplantation Proceedings. 29. 1205-1206 (1997) No. (%) 14 (45) 13 (56) 11 (64) 2 (38) 8(80) 3 (38) Reactive %011 Chimerism POD:!: SO Steroids (%) 750:!: 157 50 92 716:!: 207 77 75 536:!: 179 44 70 942:!: 236 50 50 60S:!: 2703 NA 88 467:!: 164 NA 100 0041-1345/97/$17.00 PI! S0041-1345(96)00552-0 1205 1206 ZEEVI, PAVLICK, BANAS ET AL Table 2. Results of MLR in Non 8M-Augmented Organ Transplant Recipients and Its Correlation With Incidence of Chimerism DSHI No. No. % Off Type of Transplant Transplant (%) POD::: SO Steroids Uver 23 7 (30) 886:t 109 100 Kidney 10 5 (50) 846:t 75 20 Kidney + pancreas 7 2 (28) 653 :t 103 50 Kidney + islet 2 0 0 NA Heart 9 2 (22) 752:t 190 NA Lung 6 2 (33) 515:t 23 NA specific immunomodula.tion was achieved in 50%. On the contrary, only 18 of 57 (32%) of the control patients exhibited hyporeactivity or intermediate responses to the donor (DSHI). It is noteworthy that the temporal relation-ship of monitoring was comparable in both study and control recipients (Tables 1 and 2). Liver Transplant Recipients BM-augmented liver transplant recipients developed stable DSHI within the first year posttransplantation and 13 of 15 patients retested remained DSHI at the 2-year follow-up (range 200 to 600 days). In contrast. in those who received only a liver. only three of seven recipients who exhibited DSHI previously maintained persistent immunomodulation (data not shown). Two of the BM-augmented liver recipi-ents exhibited low proliferative responses to mitogens. donors. and third-party alloantigens and were considered suppressed. The majority of study (87%) and control (100%) recipients who displayed DSHI were off pred-nisolone. while weaning from steroids was achieved in only 50% of those who were reactive in these groups (Tables 1 and 2). Furthermore. a significant lower incidence of late acute cellular rejection was witnessed in BM-augmented liver recipients who had previously exhibited DSHI as wmpared to those who were MLR reactive. The frequency of donor cell chimerism in study recipients displaying DSHI was similar to those who were reactive (87'70 and 92%. respectively). whereas the frequency of donor cell chimer-ism detected in the control group was approximately 601"0. Kidney Transplant Recipients The outcome in the BM-augmented and control kidney transplant recipients was comparahle for all the parameters tested including immune status. percent off steroids. and incidence of donor-specific chimerism (Tahles I and 2).7 Four BM-augmented kidney transplant recipients who ex-perienced late rejection episodes lost their grafts. Two of these recipients developed DSHI during the first year post-transplant hut re\,erted tn l\ILR rcactive status prior to evolvement nf the late rejection episode. ultimatelv leading to graft loss. It is noteworthy that a higher percent of BM-augmented kidney + rancreas and kidney -'- Islet recipients exhihited DSHI in comparisnn to that of control patiellls. Reactive Chimerism No. %01 Chimerism (%) (%) POD::: SO Steroids (%) 67 16 (70) 871 :t 87 56 50 60 5 (50) 674:t 346 60 75 50 5 (72) 453 :t 128 20 40 NA 2 (100) 334 :t 68 50 100 100 7 (78) 536:t 263 NA :"0(43 100 4 (67) 495 :t 16 NA 50 Thoracic Organs Most of the heart transplant recipients in the study and control group retained donor-specific responsiveness (Ta-bles 1 and 2). On the contrary, in lung allograft recipients a twofold higher incidence of induction of DSHI (62%) was observed in BM-augmented patients as compared to that of controls (33%). The frequency of donor cell chimerism was 80% in BM-augmented and nonaugmented heart and lung transplant recipients who exhibited DSHI. whereas it was only 50% in controls who were MLR reactive. Although not statistically significant. there was a trend toward a lower incidence of rejection within the first 100 days after trans-plantation in the study heart recipients as compared to similarly treated historical controls. H Bronchiolitis obliter-ans (OB). a form of chronic rejection in lung recipients. was witnessed in two of six controls and in none of the eight study patients with a follow-up of 18 months posttransplan-tation. In summary. the simultaneous infusion of donor BM cells in allograft recipients was associated with an increase in the incidence of donor cell chimerism in all organ allografts. and with a twofold increase of DSHI in liver and lung recipients. Furthermore. BM-augmented transplant recipi-ents who developed stable donor-specific hyporeactivity experienced less late allograft rejection and improved long-term outcome. REFERENCES I. Starzl TE. Demetris AJ. Murase N. et al: Lancet 339:1579, 1992 2. Starzl TE. Demctris r\J. Trucco M. et al: Hcpathology 17:1127.1993 3. Starzl TE. Demetris AJ. Murasc N. ct al: immunol Todav 1·+:326. 1993 . 4. Fontes 1'. Rao AS. D"llletris AJ. et al: Lancet 344:151. 1994 5. Zccvi A. Pavlick M. Lomharuozzi S. <:t al: Transplantation 59:tiI6. It)<)4 h. Zeevi A. Pa,llck M. LOl11harunzzi S. ct al: Transplant Proc 27:213. 1')<)5 7. Shapiro R. R.lll ,\S. Fontes P. et al: TransplantatIon 59:306. 1')95 S. Pham S\1. "':':IL,n RJ. Rao AS . .:t al: ,\nn Thome Surg hO:1015.1')')' 

Three years of follow-up bone marrow-augmented organ transplant recipients: The impact on donor-specific immune modulation

Name not available

Three years of follow-up of bone marrow augmented organ transplant recipients: the impact on donor specific immune modulation

EGIDI, MARIA FRANCESCA

Archivio della Ricerca - Università di Pisa

Three years of follow-up of bone marrow-augmented organ transplant recipients: the impact on donor-specific immune modulation

Zeevi, A

Pavlick, M

Jordan, M

Pham, S

Keenan, R

Griffith, B

Corry, R

Egidi, F

Fung, J. J

Starzl, T. E

Banas, R

Bentlejewski, C

Spichty, K

Rao, A. S

Fontes, P

Iyengar, A

Shapiro, R

Dodson, F

University of Miami: Scholarship@Miami

Transplantation Proceedings

Three years of follow-up of bone marrow-augmented organ transplant recipients : The impact on donor-specific immune modulation

http://d-scholarship.pitt.edu/5308/1/31735062133875.pdf

Three years of follow-up bone marrow-augmented organ transplant recipients: The impact on donor-specific immune modulation

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