Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses

James M. Mathew, Rolando Garcia-Morales, Laphalle Fuller, Anne Rosen, Gaetano Ciancio, George W Burke, Manuel Carreno, Donald Temple, Andreas G. Tzakis, Camillo Ricordi, Joshua Miller, Violet Esquenazi

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Abstract

Background. Even though a number of transplant centers have adopted donor-specific bone marrow cell (DBMC) infusions to enhance donor cell chimerism, to date there has been no direct evidence linking chimerism with tolerance induction in human organ transplant recipients. Methods. Cells of donor phenotype were isolated 1 year postoperatively from the peripheral blood lymphocytes and iliac crest bone marrow of 11 living-related-donor (LRD) renal transplant recipients, who had received perioperative donor bone marrow cell infusions. These recipient-derived donor (RdD) cells were characterized phenotypically by flow cytometric analysis and functionally as modulators in mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. Results. The yield of RdD cells ranged from 0.1 to 0.9% of the starting material with the majority being TcRαβ. CD3 positive T cells, a substantial percentage of which coexpressed CD28. At 1 year posttransplant almost 50% of the LRD-kidney/DBMC recipients tested so far exhibited donor-specific unresponsiveness in MLR (7/17) and CML (6/13) reactions and this trend was further enhanced at 2-3 years. In the recipients with residual positive antidonor immune responses, the RdD cells inhibited recipient antidonor MLR and CML responses significantly more strongly than freshly isolated and similarly treated iliac crest bone marrow cells from the donor. RdD cells also inhibited the MLR of the recipient to third party allogeneic stimulator cells; however, this nonspecific effect was significantly weaker than specific inhibition. We also established long-term bone marrow cultures stimulated every 2 weeks with irradiated allogeneic feeder cells, that had similar functional properties thus possibly providing us with an in vitro correlate the RdD cells. Conclusions. These results clearly support the notion that the infused donor cells play a positive role in the induction and/or maintenance of transplant tolerance.

Original languageEnglish
Pages (from-to)1675-1682
Number of pages8
JournalTransplantation
Volume70
Issue number12
StatePublished - Dec 27 2000

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Bone Marrow
Tissue Donors
Kidney
Mixed Lymphocyte Culture Test
Bone Marrow Cells
Chimerism
Living Donors
Transplants
Transplant Recipients
Feeder Cells
Maintenance
Lymphocytes
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Transplantation
  • Immunology

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Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses. / Mathew, James M.; Garcia-Morales, Rolando; Fuller, Laphalle; Rosen, Anne; Ciancio, Gaetano; Burke, George W; Carreno, Manuel; Temple, Donald; Tzakis, Andreas G.; Ricordi, Camillo; Miller, Joshua; Esquenazi, Violet.

In: Transplantation, Vol. 70, No. 12, 27.12.2000, p. 1675-1682.

Research output: Contribution to journalArticle

Mathew, JM, Garcia-Morales, R, Fuller, L, Rosen, A, Ciancio, G, Burke, GW, Carreno, M, Temple, D, Tzakis, AG, Ricordi, C, Miller, J & Esquenazi, V 2000, 'Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses', Transplantation, vol. 70, no. 12, pp. 1675-1682.
Mathew, James M. ; Garcia-Morales, Rolando ; Fuller, Laphalle ; Rosen, Anne ; Ciancio, Gaetano ; Burke, George W ; Carreno, Manuel ; Temple, Donald ; Tzakis, Andreas G. ; Ricordi, Camillo ; Miller, Joshua ; Esquenazi, Violet. / Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses. In: Transplantation. 2000 ; Vol. 70, No. 12. pp. 1675-1682.
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abstract = "Background. Even though a number of transplant centers have adopted donor-specific bone marrow cell (DBMC) infusions to enhance donor cell chimerism, to date there has been no direct evidence linking chimerism with tolerance induction in human organ transplant recipients. Methods. Cells of donor phenotype were isolated 1 year postoperatively from the peripheral blood lymphocytes and iliac crest bone marrow of 11 living-related-donor (LRD) renal transplant recipients, who had received perioperative donor bone marrow cell infusions. These recipient-derived donor (RdD) cells were characterized phenotypically by flow cytometric analysis and functionally as modulators in mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. Results. The yield of RdD cells ranged from 0.1 to 0.9{\%} of the starting material with the majority being TcRαβ. CD3 positive T cells, a substantial percentage of which coexpressed CD28. At 1 year posttransplant almost 50{\%} of the LRD-kidney/DBMC recipients tested so far exhibited donor-specific unresponsiveness in MLR (7/17) and CML (6/13) reactions and this trend was further enhanced at 2-3 years. In the recipients with residual positive antidonor immune responses, the RdD cells inhibited recipient antidonor MLR and CML responses significantly more strongly than freshly isolated and similarly treated iliac crest bone marrow cells from the donor. RdD cells also inhibited the MLR of the recipient to third party allogeneic stimulator cells; however, this nonspecific effect was significantly weaker than specific inhibition. We also established long-term bone marrow cultures stimulated every 2 weeks with irradiated allogeneic feeder cells, that had similar functional properties thus possibly providing us with an in vitro correlate the RdD cells. Conclusions. These results clearly support the notion that the infused donor cells play a positive role in the induction and/or maintenance of transplant tolerance.",
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T1 - Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses

AU - Mathew, James M.

AU - Garcia-Morales, Rolando

AU - Fuller, Laphalle

AU - Rosen, Anne

AU - Ciancio, Gaetano

AU - Burke, George W

AU - Carreno, Manuel

AU - Temple, Donald

AU - Tzakis, Andreas G.

AU - Ricordi, Camillo

AU - Miller, Joshua

AU - Esquenazi, Violet

PY - 2000/12/27

Y1 - 2000/12/27

N2 - Background. Even though a number of transplant centers have adopted donor-specific bone marrow cell (DBMC) infusions to enhance donor cell chimerism, to date there has been no direct evidence linking chimerism with tolerance induction in human organ transplant recipients. Methods. Cells of donor phenotype were isolated 1 year postoperatively from the peripheral blood lymphocytes and iliac crest bone marrow of 11 living-related-donor (LRD) renal transplant recipients, who had received perioperative donor bone marrow cell infusions. These recipient-derived donor (RdD) cells were characterized phenotypically by flow cytometric analysis and functionally as modulators in mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. Results. The yield of RdD cells ranged from 0.1 to 0.9% of the starting material with the majority being TcRαβ. CD3 positive T cells, a substantial percentage of which coexpressed CD28. At 1 year posttransplant almost 50% of the LRD-kidney/DBMC recipients tested so far exhibited donor-specific unresponsiveness in MLR (7/17) and CML (6/13) reactions and this trend was further enhanced at 2-3 years. In the recipients with residual positive antidonor immune responses, the RdD cells inhibited recipient antidonor MLR and CML responses significantly more strongly than freshly isolated and similarly treated iliac crest bone marrow cells from the donor. RdD cells also inhibited the MLR of the recipient to third party allogeneic stimulator cells; however, this nonspecific effect was significantly weaker than specific inhibition. We also established long-term bone marrow cultures stimulated every 2 weeks with irradiated allogeneic feeder cells, that had similar functional properties thus possibly providing us with an in vitro correlate the RdD cells. Conclusions. These results clearly support the notion that the infused donor cells play a positive role in the induction and/or maintenance of transplant tolerance.

AB - Background. Even though a number of transplant centers have adopted donor-specific bone marrow cell (DBMC) infusions to enhance donor cell chimerism, to date there has been no direct evidence linking chimerism with tolerance induction in human organ transplant recipients. Methods. Cells of donor phenotype were isolated 1 year postoperatively from the peripheral blood lymphocytes and iliac crest bone marrow of 11 living-related-donor (LRD) renal transplant recipients, who had received perioperative donor bone marrow cell infusions. These recipient-derived donor (RdD) cells were characterized phenotypically by flow cytometric analysis and functionally as modulators in mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. Results. The yield of RdD cells ranged from 0.1 to 0.9% of the starting material with the majority being TcRαβ. CD3 positive T cells, a substantial percentage of which coexpressed CD28. At 1 year posttransplant almost 50% of the LRD-kidney/DBMC recipients tested so far exhibited donor-specific unresponsiveness in MLR (7/17) and CML (6/13) reactions and this trend was further enhanced at 2-3 years. In the recipients with residual positive antidonor immune responses, the RdD cells inhibited recipient antidonor MLR and CML responses significantly more strongly than freshly isolated and similarly treated iliac crest bone marrow cells from the donor. RdD cells also inhibited the MLR of the recipient to third party allogeneic stimulator cells; however, this nonspecific effect was significantly weaker than specific inhibition. We also established long-term bone marrow cultures stimulated every 2 weeks with irradiated allogeneic feeder cells, that had similar functional properties thus possibly providing us with an in vitro correlate the RdD cells. Conclusions. These results clearly support the notion that the infused donor cells play a positive role in the induction and/or maintenance of transplant tolerance.

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