Stem cell mobilization and collection for induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys

Ognjenka Nadazdin, Gregory A Abrahamian, Svjetlan Boskovic, Rex Neal Smith, David A. Schoenfeld, Joren C. Madsen, Robert B. Colvin, David H. Sachs, A. Benedict Cosimi, Tatsuo Kawai

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: We have previously observed that donor bone marrow hematopoietic stem cells successfully induce transient mixed chimerism and renal allograft tolerance following non-myeloablative conditioning of the recipient. Stem cells isolated from the peripheral blood (PBSC) may provide similar benefits. We sought to determine the most effective method of mobilizing PBSC for this approach and the effects of differing conditioning regimens on their engraftment. Methods: A standard dose (10 μg/kg) or high dose (100 μg/kg) of granulocyte colony-stimulating factor (GCSF) with or without stem cell factor (SCF) was administered to the donor, and PBSC were collected by leukapheresis. Cynomolgus monkey recipients underwent a nonmyeloablative conditioning regimen (total body irradiation, thymic irradiation, and ATG) with splenectomy (splenectomy group) or a short course of anti-CD154 antibody (aCD154) (aCD154 group). Recipients then received combined kidney and PBSC transplantation and a 1-mo post-transplant course of cyclosporine. Results: Treatments with either two cytokines (GCSF+SCF) or high dose GCSF provided significantly more hematopoietic progenitor cells than standard dose GCSF alone. Recipients in the aCD154 group developed significantly higher myeloid and lymphoid chimerism (P < 0.0001 and P = 0.0002, respectively) than those in the splenectomy group. Longer term renal allograft survival without immunosuppression was also observed in the aCD154 group, while two of three recipients in the splenectomy group rejected their allografts soon after discontinuation of immunosuppression. Conclusions: Protocols including administration of two cytokines (GCSF + SCF) or high dose GCSF alone significantly mobilized more PBSC than standard dose GCSF alone. The recipients of PBSC consistently developed excellent chimerism and survived long-term without immunosuppression, when treated with CD154 blockade.

Original languageEnglish (US)
Pages (from-to)294-300
Number of pages7
JournalJournal of Surgical Research
Volume168
Issue number2
DOIs
StatePublished - Jun 15 2011

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Hematopoietic Stem Cell Mobilization
Transplantation Tolerance
Chimerism
Macaca fascicularis
Granulocyte Colony-Stimulating Factor
Kidney
Splenectomy
Stem Cell Factor
Anti-Idiotypic Antibodies
Immunosuppression
Hematopoietic Stem Cells
Allografts
Cytokines
Leukapheresis
Whole-Body Irradiation
Kidney Transplantation
Cyclosporine
Bone Marrow
Transplants

Keywords

  • kidney transplantation
  • leukapheresis
  • mixed chimerism
  • nonhuman primates
  • peripheral blood stem cell transplantation
  • tolerance

ASJC Scopus subject areas

  • Surgery

Cite this

Nadazdin, O., Abrahamian, G. A., Boskovic, S., Smith, R. N., Schoenfeld, D. A., Madsen, J. C., ... Kawai, T. (2011). Stem cell mobilization and collection for induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys. Journal of Surgical Research, 168(2), 294-300. https://doi.org/10.1016/j.jss.2010.02.027

Stem cell mobilization and collection for induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys. / Nadazdin, Ognjenka; Abrahamian, Gregory A; Boskovic, Svjetlan; Smith, Rex Neal; Schoenfeld, David A.; Madsen, Joren C.; Colvin, Robert B.; Sachs, David H.; Cosimi, A. Benedict; Kawai, Tatsuo.

In: Journal of Surgical Research, Vol. 168, No. 2, 15.06.2011, p. 294-300.

Research output: Contribution to journalArticle

Nadazdin, O, Abrahamian, GA, Boskovic, S, Smith, RN, Schoenfeld, DA, Madsen, JC, Colvin, RB, Sachs, DH, Cosimi, AB & Kawai, T 2011, 'Stem cell mobilization and collection for induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys', Journal of Surgical Research, vol. 168, no. 2, pp. 294-300. https://doi.org/10.1016/j.jss.2010.02.027
Nadazdin, Ognjenka ; Abrahamian, Gregory A ; Boskovic, Svjetlan ; Smith, Rex Neal ; Schoenfeld, David A. ; Madsen, Joren C. ; Colvin, Robert B. ; Sachs, David H. ; Cosimi, A. Benedict ; Kawai, Tatsuo. / Stem cell mobilization and collection for induction of mixed chimerism and renal allograft tolerance in cynomolgus monkeys. In: Journal of Surgical Research. 2011 ; Vol. 168, No. 2. pp. 294-300.
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abstract = "Background: We have previously observed that donor bone marrow hematopoietic stem cells successfully induce transient mixed chimerism and renal allograft tolerance following non-myeloablative conditioning of the recipient. Stem cells isolated from the peripheral blood (PBSC) may provide similar benefits. We sought to determine the most effective method of mobilizing PBSC for this approach and the effects of differing conditioning regimens on their engraftment. Methods: A standard dose (10 μg/kg) or high dose (100 μg/kg) of granulocyte colony-stimulating factor (GCSF) with or without stem cell factor (SCF) was administered to the donor, and PBSC were collected by leukapheresis. Cynomolgus monkey recipients underwent a nonmyeloablative conditioning regimen (total body irradiation, thymic irradiation, and ATG) with splenectomy (splenectomy group) or a short course of anti-CD154 antibody (aCD154) (aCD154 group). Recipients then received combined kidney and PBSC transplantation and a 1-mo post-transplant course of cyclosporine. Results: Treatments with either two cytokines (GCSF+SCF) or high dose GCSF provided significantly more hematopoietic progenitor cells than standard dose GCSF alone. Recipients in the aCD154 group developed significantly higher myeloid and lymphoid chimerism (P < 0.0001 and P = 0.0002, respectively) than those in the splenectomy group. Longer term renal allograft survival without immunosuppression was also observed in the aCD154 group, while two of three recipients in the splenectomy group rejected their allografts soon after discontinuation of immunosuppression. Conclusions: Protocols including administration of two cytokines (GCSF + SCF) or high dose GCSF alone significantly mobilized more PBSC than standard dose GCSF alone. The recipients of PBSC consistently developed excellent chimerism and survived long-term without immunosuppression, when treated with CD154 blockade.",
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AU - Abrahamian, Gregory A

AU - Boskovic, Svjetlan

AU - Smith, Rex Neal

AU - Schoenfeld, David A.

AU - Madsen, Joren C.

AU - Colvin, Robert B.

AU - Sachs, David H.

AU - Cosimi, A. Benedict

AU - Kawai, Tatsuo

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N2 - Background: We have previously observed that donor bone marrow hematopoietic stem cells successfully induce transient mixed chimerism and renal allograft tolerance following non-myeloablative conditioning of the recipient. Stem cells isolated from the peripheral blood (PBSC) may provide similar benefits. We sought to determine the most effective method of mobilizing PBSC for this approach and the effects of differing conditioning regimens on their engraftment. Methods: A standard dose (10 μg/kg) or high dose (100 μg/kg) of granulocyte colony-stimulating factor (GCSF) with or without stem cell factor (SCF) was administered to the donor, and PBSC were collected by leukapheresis. Cynomolgus monkey recipients underwent a nonmyeloablative conditioning regimen (total body irradiation, thymic irradiation, and ATG) with splenectomy (splenectomy group) or a short course of anti-CD154 antibody (aCD154) (aCD154 group). Recipients then received combined kidney and PBSC transplantation and a 1-mo post-transplant course of cyclosporine. Results: Treatments with either two cytokines (GCSF+SCF) or high dose GCSF provided significantly more hematopoietic progenitor cells than standard dose GCSF alone. Recipients in the aCD154 group developed significantly higher myeloid and lymphoid chimerism (P < 0.0001 and P = 0.0002, respectively) than those in the splenectomy group. Longer term renal allograft survival without immunosuppression was also observed in the aCD154 group, while two of three recipients in the splenectomy group rejected their allografts soon after discontinuation of immunosuppression. Conclusions: Protocols including administration of two cytokines (GCSF + SCF) or high dose GCSF alone significantly mobilized more PBSC than standard dose GCSF alone. The recipients of PBSC consistently developed excellent chimerism and survived long-term without immunosuppression, when treated with CD154 blockade.

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