Prevention of Insulitis and Diabetes Onset by Treatment With Complete Freund's Adjuvant in NOD Mice

Abstract

In studies of immune cell defects in autoimmune diabetes mellitus, we observed that complete Freund's adjuvant (CFA) prevented the onset of diabetes when injected into 8- to 10-wk-old prediabetic nonobese diabetic (NOD) mice. The prevalence of the onset of diabetes in the CFA-injected versus uninjected NOD mice was 2 of 81 (2.5%) vs. 231 of 379 (61%) among females and 2 of 44 (4.5%) vs. 83 of 336 (25%) among males, respectively. The incidence of histologically identifiable insulitis was significantly reduced in CFA-treated prediabetic female NOD mice (18%) compared with the incidence in female age-matched controls (70%). Splenocytes or Mac-(1+)-enriched splenocytes from CFA-treated NOD mice, when cotransferred with splenocytes from diabetic mice, reduced the incidence of diabetes provoked by diabetic splenocytes in vivo. In the spleen, CFA injection induced sustained increases in cell proliferation and an associated major increase in the numbers of an immature cell type that expressed the Mac-1 surface antigen. In CFA-treated NOD mice, lymphocytes derived from the spleen failed to respond in vitro to stimulation by the mitogen concanavalin A or by anti-CD3. When cocultured, Mac-1+ cells, enriched from the splenocytes of CFA-treated mice, suppressed concanavalin A- or anti-CD3-induced proliferation of T lymphocytes derived from either the spleen or thymus of untreated NOD mice. Therefore, treatment with CFA prevents the development of diabetes, and concomitantly, insulitis while stimulating the generation of splenic suppressor cells that are capable of suppressing diabetogenic T-lymphocyte function in vivo and in vitro.

Activated NKT Cells Inhibit Autoimmune Diabetes through Tolerogenic Recruitment of Dendritic Cells to Pancreatic Lymph Nodes

“…Our results would seem to conflict with a previous report in which ␣-GalCer activation of NKT cells also induced DC maturation, but this switched them to an immunogenic rather than a tolerogenic status (15). However, it should be noted while CFA is normally used to boost immune responses to coadministered Ags in part through the induction of DC maturation, it efficiently blocks T1D development in NOD mice (45). In addition, ex vivo manipulated mature NOD DCs possess higher T1D-protective capacity over their immature counterparts (46,47).…”

MHC Class I-Restricted Determinants on the Glutamic Acid Decarboxylase 65 Molecule Induce Spontaneous CTL Activity

“…Exposure to CFA has been shown to interfere with the progression of IDDM in NOD mice (31,32). We wanted to determine whether the protective effect produced by CFA immunization could influence the spontaneous CTL response to p206 or p546.…”

Echovirus Epidemics, Autoimmunity, and Type 1 Diabetes

“…More interesting, prevention of T1D in NOD mice has been achieved by treatment with a variety of immune enhancers, including complete Freund's adjuvant (McInerney et al, 1991), immunogenic but not tolerated peptides (Vaysburd et al, 1995), Mycobacterium avium (Martins & Aguas, 1996), Lactobacillus casei (Matsuzaki et al, 1997), Mycobacterium leprae (Nomaguchi et al, 2002), lymphocytic choriomeningitis virus (LCMV) (Christen et al, 2004). T1D prevention has also been achieved by exposure to helminthes or products from these organisms, however, it is important to recognize that not all infecting agents, parasites or their products are able to induce this effect (Cooke, 2009).…”