Induction of Insulitis by Adoptive Transfer With L3T4+ Lyt2− T-Lymphocytes in T-Lymphocyte–Depleted NOD Mice

Abstract

To clarify the pathogenesis of insulitis in the nonobese diabetic (NOD) mouse, an animal model for human insulin-dependent diabetes mellitus, T-lymphocyte-depleted NOD mice (B mice) were adoptively transferred with spleen and lymph node cells from cyclophosphamide-treated NOD mice after separating the cells with monoclonal antibodies against various T-lymphocyte surface antigens plus complement. Light-microscopic and immunohistochemical studies were also performed to investigate the lymphocytic infiltrations. The incidence of insulitis detected in B mice was much lower when compared with that of the lesion naturally occurring in the NOD mouse. However, higher incidence of insulitis was inducible in B mice by transferring unfractionated lymphoid cells from NOD mice. When the Thy1+ cell-depleted fraction was transferred into the B mice, no increase in the incidence of insulitis was observed. The Lyt1+ or L3T4+ cell-eliminated fraction was also unable to transfer insulitis. Conversely, donor cells depleted of Lyt2+ components successfully induced insulitis in the recipient B mice. These data were consistent with the immunohistochemical study, which showed that the main phenotype of the cells infiltrating the islets was L3T4+. These results suggest the importance of L3T4+Lyt2- T-lymphocytes in the pathogenesis of insulitis in NOD mice.

Viruses as therapeutic agents. I. Treatment of nonobese insulin-dependent diabetes mice with virus prevents insulin-dependent diabetes mellitus while maintaining general immune competence.

“…are consistent with the report of Shizuru et al (36), whose use of mAbs against the CD4 determinant prevented lymphocytic infiltration, eliminated destruction ofinsulinproducing a cells, and blocked IDDM in NOD mice (36). Similarly, several investigators have shown a selective role for CD4+ lymphocytes in the ability to transfer IDDM in NOD mice (37)(38)(39), while others noted a combined or accelerated role with CD4+ and CD8+ lymphocytes (22,40,41 The involvement of CD4+ cells in offsetting this genetic susceptibility to disease of LCMV infected NOD mice is not associated with generalized immunosuppression. Despite carrying LCMV and escaping from IDDM, these mice are nevertheless able to make immune responses to a wide variety of antigens all dependent on CD4 function .…”

β2-Microglobulin–Deficient NOD Mice Do Not Develop Insulitis or Diabetes

“…On the one hand, cloned islet-reactive NOD CD4 + T-cells have been shown to mediate rejection of islet cell grafts (3,4) and to transfer diabetes to NOD-scid/scid mice (5). In contrast, using freshly isolated uncloned T-cells, most groups report that both CD4 + and CD8 + T-cells are necessary to transfer diabetes and that CD4 + T-cells alone transfer only insulitis to recipients (6)(7)(8). We (7) and Bendelac et al (8) proposed an interaction between the two subsets of cells in which CD4 + cells were involved in the homing and activation of CD8 + islet-reactive cells, the physiologically relevant effectors of p-cell destruction.…”

Heterogenous graft rejection pathways in class I major histocompatibility complex-disparate combinations and their differential susceptibility to immunomodulation induced by intravenous presensitization with relevant alloantigens.

“…In combinations with only class I MHC disparity, the former two Th cell subsets are activated to recognize allo class I MHC antigens, although predominatly allo class I MHC-restricted CD8+ Th cells function in the B6-bml combination where class I disparity is generated by a simple mutation in a class I MHC gene (16,18) . In addition to this classical CD8+ CTIrinvolved pathway, it is likely that tissue destruction/graft rejection in transplantation immunity, as well as tumor immunity and autoimmunity, is also induced by an alternate immune pathway(s) (28)(29)(30)(31)(32)(33)(34)(35)(36) . The cellular and molecular mechanisms involved in such pathway(s) remain to be determined.…”