Distinct requirements for achievement of allotolerance versus reversal of autoimmunity via nonmyeloablative mixed chimerism induction in NOD mice

Boris Nikolic, Takashi Onoe, Yasuo Takeuchi, Zain I Khalpey, Valeria Primo, Igor Leykin, R. Neal Smith, Megan Sykes

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

OBJECTIVES: Mixed hematopoietic chimerism is associated with islet allograft tolerance and may reverse autoimmunity. We developed low intensity regimens for the induction of mixed chimerism and examined the effects on autoimmunity in prediabetic nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS: NOD mice received various combinations of total body irradiation, anti-CD154, anti-CD8α, anti-CD4, and anti-Thy1.2 monoclonal antibodies, with or without transplantation of C57BL/6 bone marrow cells and were followed up for development of diabetes, chimerism, and donor skin graft survival. Autoimmunity was assessed by histologic examination of salivary glands and pancreata. RESULTS: Although conditioning alone prevented or delayed the onset of diabetes, stable mixed chimerism was required for the reversal of isletitis. Mixed chimerism and skin graft tolerance were achieved in NOD mice receiving anti-CD154 with bone marrow transplantation as the means of tolerizing peripheral CD4 T cells to alloantigens. However, isletitis was not reversed in allotolerant mixed chimeras prepared with this regimen. CONCLUSIONS: Partial depletion of peripheral autoreactive NOD CD4 T cells is needed to achieve full reversal of isletitis by mixed chimerism induction from a protective donor strain, but it is not required for induction of specific tolerance to donor alloantigens. Thus, the requirements for tolerizing alloreactive and autoreactive NOD CD4 cells are distinct. copyright

Original languageEnglish (US)
Pages (from-to)23-32
Number of pages10
JournalTransplantation
Volume89
Issue number1
DOIs
StatePublished - Jan 2010
Externally publishedYes

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Inbred NOD Mouse
Chimerism
Autoimmunity
Transplantation Tolerance
Isoantigens
T-Lymphocytes
Skin
Whole-Body Irradiation
Graft Survival
Salivary Glands
Bone Marrow Transplantation
Bone Marrow Cells
Pancreas
Research Design
Transplantation
Monoclonal Antibodies

Keywords

  • Immunology
  • Tolerance
  • Transplantation.

ASJC Scopus subject areas

  • Transplantation

Cite this

Distinct requirements for achievement of allotolerance versus reversal of autoimmunity via nonmyeloablative mixed chimerism induction in NOD mice. / Nikolic, Boris; Onoe, Takashi; Takeuchi, Yasuo; Khalpey, Zain I; Primo, Valeria; Leykin, Igor; Smith, R. Neal; Sykes, Megan.

In: Transplantation, Vol. 89, No. 1, 01.2010, p. 23-32.

Research output: Contribution to journalArticle

Nikolic, Boris ; Onoe, Takashi ; Takeuchi, Yasuo ; Khalpey, Zain I ; Primo, Valeria ; Leykin, Igor ; Smith, R. Neal ; Sykes, Megan. / Distinct requirements for achievement of allotolerance versus reversal of autoimmunity via nonmyeloablative mixed chimerism induction in NOD mice. In: Transplantation. 2010 ; Vol. 89, No. 1. pp. 23-32.
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AU - Takeuchi, Yasuo

AU - Khalpey, Zain I

AU - Primo, Valeria

AU - Leykin, Igor

AU - Smith, R. Neal

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N2 - OBJECTIVES: Mixed hematopoietic chimerism is associated with islet allograft tolerance and may reverse autoimmunity. We developed low intensity regimens for the induction of mixed chimerism and examined the effects on autoimmunity in prediabetic nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS: NOD mice received various combinations of total body irradiation, anti-CD154, anti-CD8α, anti-CD4, and anti-Thy1.2 monoclonal antibodies, with or without transplantation of C57BL/6 bone marrow cells and were followed up for development of diabetes, chimerism, and donor skin graft survival. Autoimmunity was assessed by histologic examination of salivary glands and pancreata. RESULTS: Although conditioning alone prevented or delayed the onset of diabetes, stable mixed chimerism was required for the reversal of isletitis. Mixed chimerism and skin graft tolerance were achieved in NOD mice receiving anti-CD154 with bone marrow transplantation as the means of tolerizing peripheral CD4 T cells to alloantigens. However, isletitis was not reversed in allotolerant mixed chimeras prepared with this regimen. CONCLUSIONS: Partial depletion of peripheral autoreactive NOD CD4 T cells is needed to achieve full reversal of isletitis by mixed chimerism induction from a protective donor strain, but it is not required for induction of specific tolerance to donor alloantigens. Thus, the requirements for tolerizing alloreactive and autoreactive NOD CD4 cells are distinct. copyright

AB - OBJECTIVES: Mixed hematopoietic chimerism is associated with islet allograft tolerance and may reverse autoimmunity. We developed low intensity regimens for the induction of mixed chimerism and examined the effects on autoimmunity in prediabetic nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS: NOD mice received various combinations of total body irradiation, anti-CD154, anti-CD8α, anti-CD4, and anti-Thy1.2 monoclonal antibodies, with or without transplantation of C57BL/6 bone marrow cells and were followed up for development of diabetes, chimerism, and donor skin graft survival. Autoimmunity was assessed by histologic examination of salivary glands and pancreata. RESULTS: Although conditioning alone prevented or delayed the onset of diabetes, stable mixed chimerism was required for the reversal of isletitis. Mixed chimerism and skin graft tolerance were achieved in NOD mice receiving anti-CD154 with bone marrow transplantation as the means of tolerizing peripheral CD4 T cells to alloantigens. However, isletitis was not reversed in allotolerant mixed chimeras prepared with this regimen. CONCLUSIONS: Partial depletion of peripheral autoreactive NOD CD4 T cells is needed to achieve full reversal of isletitis by mixed chimerism induction from a protective donor strain, but it is not required for induction of specific tolerance to donor alloantigens. Thus, the requirements for tolerizing alloreactive and autoreactive NOD CD4 cells are distinct. copyright

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