Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates

Jose R. Torrealba, Masaaki Katayama, John H. Fechner, Ewa Jankowska-Gan, Satoshi Kusaka, Qingyong Xu, Jacqueline M. Schultz, Terry D. Oberley, Huaizhong Hu, Majed M. Hamawy, Margreet Jonker, Jacqueline Wubben, Gaby Doxiadis, Ronald Bontrop, William J. Burlingham, Stuart J. Knechtle

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Abstract

Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-β+ interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/ disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-β1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-β1. Peripheral leukocytes from rejecting monkeys lacking TGF-β1+ allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity transvivo assays. In contrast, allograft acceptors with TGF-β1+ infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-β1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8 + and CD4+ interstitial T cell infiltrates, but only the CD4+ subset included cells costaining for TGF-β1. Our data support the hypothesis that the recruitment of CD4+ T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.

Original languageEnglish (US)
Pages (from-to)5753-5764
Number of pages12
JournalJournal of Immunology
Volume172
Issue number9
StatePublished - May 1 2004

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Regulatory T-Lymphocytes
Macaca mulatta
Allografts
Transplants
Kidney
Delayed Hypersensitivity
Haplorhini
Isoantigens
Graft Rejection
Interleukin-10
Immunosuppression
Primates
Histology
Leukocytes
T-Lymphocytes

ASJC Scopus subject areas

  • Immunology

Cite this

Torrealba, J. R., Katayama, M., Fechner, J. H., Jankowska-Gan, E., Kusaka, S., Xu, Q., ... Knechtle, S. J. (2004). Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates. Journal of Immunology, 172(9), 5753-5764.

Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates. / Torrealba, Jose R.; Katayama, Masaaki; Fechner, John H.; Jankowska-Gan, Ewa; Kusaka, Satoshi; Xu, Qingyong; Schultz, Jacqueline M.; Oberley, Terry D.; Hu, Huaizhong; Hamawy, Majed M.; Jonker, Margreet; Wubben, Jacqueline; Doxiadis, Gaby; Bontrop, Ronald; Burlingham, William J.; Knechtle, Stuart J.

In: Journal of Immunology, Vol. 172, No. 9, 01.05.2004, p. 5753-5764.

Research output: Contribution to journalArticle

Torrealba, JR, Katayama, M, Fechner, JH, Jankowska-Gan, E, Kusaka, S, Xu, Q, Schultz, JM, Oberley, TD, Hu, H, Hamawy, MM, Jonker, M, Wubben, J, Doxiadis, G, Bontrop, R, Burlingham, WJ & Knechtle, SJ 2004, 'Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates', Journal of Immunology, vol. 172, no. 9, pp. 5753-5764.
Torrealba, Jose R. ; Katayama, Masaaki ; Fechner, John H. ; Jankowska-Gan, Ewa ; Kusaka, Satoshi ; Xu, Qingyong ; Schultz, Jacqueline M. ; Oberley, Terry D. ; Hu, Huaizhong ; Hamawy, Majed M. ; Jonker, Margreet ; Wubben, Jacqueline ; Doxiadis, Gaby ; Bontrop, Ronald ; Burlingham, William J. ; Knechtle, Stuart J. / Metastable Tolerance to Rhesus Monkey Renal Transplants Is Correlated with Allograft TGF-β1+CD4+ T Regulatory Cell Infiltrates. In: Journal of Immunology. 2004 ; Vol. 172, No. 9. pp. 5753-5764.
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abstract = "Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-β+ interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/ disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-β1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-β1. Peripheral leukocytes from rejecting monkeys lacking TGF-β1+ allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity transvivo assays. In contrast, allograft acceptors with TGF-β1+ infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-β1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8 + and CD4+ interstitial T cell infiltrates, but only the CD4+ subset included cells costaining for TGF-β1. Our data support the hypothesis that the recruitment of CD4+ T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.",
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AU - Hamawy, Majed M.

AU - Jonker, Margreet

AU - Wubben, Jacqueline

AU - Doxiadis, Gaby

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