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


METHODS
NOD mice received various combinations of total body irradiation, anti-CD154, anti-CD8alpha, 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.
Nikolic
Boris
B
Nephrology Division, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Onoe
Takashi
T
Takeuchi
Yasuo
Y
Khalpey
Zain
Z
Primo
Valeria
V
Leykin
Igor
I
Smith
R Neal
RN
Sykes
Megan
M
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D016026:Bone Marrow Transplantation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology / Q000528:radiation effects; D016827:CD8 Antigens / Q000276:immunology / Q000528:radiation effects; D005260:Female; D005434:Flow Cytometry; D007515:Islets of Langerhans / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD / Q000276:immunology*; D008815:Mice, Inbred Strains; D011236:Prediabetic State / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology*; D018800:Thy-1 Antigens / Q000276:immunology / Q000528:radiation effects; D018183:Transplantation Chimera / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*; D014916:Whole-Body Irradiation
D016827:CD8 Antigens; D007519:Isoantigens; D018800:Thy-1 Antigens; D023201:CD40 Ligand