Acquired allo-tolerance to major or minor histocompatibility antigens indifferently contributes to preventing diabetes development in non-obese diabetic (NOD) mice.
Diabetes in NOD mice represents the end stage of a genetically-programmed autoimmune process mediated by T lymphocytes and directed against insulin-producing beta cells. We have shown in a previous study that the course of the disease is significantly inhibited in NOD mice which have been made tolerant at birth to foreign histocompatibility antigens. This early T cell manipulation results in a significant delay of disease onset, reduced overall incidence and less severe alterations of islet cells. In order to characterize better the nature of the foreign tolerogenic determinants responsible for this protection, we have now examined separately the contribution of MHC and non-MHC antigens. Two lines of congenic mice were used as donors of tolerogenic cells, NOD.H-2b, which differ from NOD by the MHC-encoded antigens only, and B10.H-2g7, which differ by all the minor histocompatibility antigens encoded by the B10 background, but which share with NOD mice the same MHC haplotype. Our results show that NOD recipients of F1 semi-compatible cells become specifically tolerant to the set of alloantigens to which they were neonatally exposed. Unresponsiveness, assessed by lack of CTL generation, is profound and specific. Yet, despite the fact that distinct sets of alloreactive T cell precursors are silenced, mice made tolerant indifferently to major or minor histocompatibility antigens are significantly protected against overt diabetes. These results could mean that each set of MHC and non-MHC encoded determinants can independently cross-tolerize a sufficient proportion of the autoreactive repertoire to slow the natural course of the disease. Alternatively, neonatally-acquired tolerance might induce polyclonal activation of the immune system resulting in the suppression or the immunodeviation of potentially harmful, autoreactive T cell clones.
Carnaud
C
C
INSERM U 25, Hôpital Necker, Paris, France.
Legrand
B
B
Olivi
M
M
Peterson
L B
LB
Wicker
L S
LS
Bach
J F
JF
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D006649:Histocompatibility Antigens / Q000276:immunology*; D007108:Immune Tolerance; D007519:Isoantigens / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D015778:Minor Histocompatibility Antigens / Q000276:immunology*
D006649:Histocompatibility Antigens; D007519:Isoantigens; D015778:Minor Histocompatibility Antigens