Genetics of the BB rat: association of autoimmune disorders (diabetes, insulitis, and thyroiditis) with lymphopenia and major histocompatibility complex class II

The BB/Wor rat develops spontaneous autoimmune diabetes mellitus and also frequently develops lymphocytic thyroiditis. To clarify the role of T cell lymphopenia and the major histocompatibility complex (MHC) in the development of these autoimmune disorders, we studied back-cross animals between the inbred thyroiditis and diabetes-prone BBNB/Wor subline (MHC RT1.AuBuDuCu) and three nonlymphopenic MHC-congenic rat strains: PVG.RT.1u (RT1.AuBuDuCu), PVG.R8 (RT1.AaBuDuCu), and PVG.R23 (RT1.AuBaDaCav1). We observed that 1) lymphopenia is absolutely required for the development of spontaneous diabetes and insulitis, and is usually associated with the development of thyroiditis; 2) the MHC region to the right of the class I RT1.A locus is strongly correlated with diabetes and insulitis; and 3) this region is also significantly associated with the development of thyroiditis, but the susceptibility of certain MHC class II alleles (u and a) for disease development is distinct for insulitis and thyroiditis. Furthermore, no recombination was observed between lymphopenia (lyp) and the neuropeptide Y (Npy) gene polymorphism, which confirmed that lyp maps very close to Npy. The present data suggest that spontaneous insulitis and thyroiditis in the BB/Wor rat develop through common immune defects involving T cell lymphopenia, but do not always segregate together due to disease-specific interactions with the MHC class II-linked genes

Salicylate prevents virus-induced type 1 diabetes in the BBDR rat.

Epidemiologic and clinical evidence suggests that virus infection plays an important role in human type 1 diabetes pathogenesis. We used the virus-inducible BioBreeding Diabetes Resistant (BBDR) rat to investigate the ability of sodium salicylate, a non-steroidal anti-inflammatory drug (NSAID), to modulate development of type 1 diabetes. BBDR rats treated with Kilham rat virus (KRV) and polyinosinic:polycytidylic acid (pIC, a TLR3 agonist) develop diabetes at nearly 100% incidence by ~2 weeks. We found distinct temporal profiles of the proinflammatory serum cytokines, IL-1β, IL-6, IFN-γ, IL-12, and haptoglobin (an acute phase protein) in KRV+pIC treated rats. Significant elevations of IL-1β and IL-12, coupled with sustained elevations of haptoglobin, were specific to KRV+pIC and not found in rats co-treated with pIC and H1, a non-diabetogenic virus. Salicylate administered concurrently with KRV+pIC inhibited the elevations in IL-1β, IL-6, IFN-γ and haptoglobin almost completely, and reduced IL-12 levels significantly. Salicylate prevented diabetes in a dose-dependent manner, and diabetes-free animals had no evidence of insulitis. Our data support an important role for innate immunity in virus-induced type 1 diabetes pathogenesis. The ability of salicylate to prevent diabetes in this robust animal model demonstrates its potential use to prevent or attenuate human autoimmune diabetes

A DNA vaccine prime followed by a liposome-encapsulated protein boost confers enhanced mucosal immune responses and protection

A variety of DNA vaccine prime and recombinant viral boost immunization strategies have been developed to enhance immune responses in humans, but inherent limitations to these strategies exist. There is still an overwhelming need to develop safe and effective approaches that raise broad humoral and T cell-mediated immune responses systemically and on mucosal surfaces. We have developed a novel mucosal immunization regimen that precludes the use of viral vectors yet induces potent T cell responses. Using hepatitis B surface Ag (HBsAg), we observed that vaccination of BALB/c mice with an i.m. HBsAg-DNA vaccine prime followed by an intranasal boost with HBsAg protein encapsulated in biologically inert liposomes enhanced humoral and T cell immune responses, particularly on mucosal surfaces. Intranasal live virus challenge with a recombinant vaccinia virus expressing HBsAg revealed a correlation between T cell immune responses and protection of immunized mice. A shortened immunization protocol was developed that was successful in both adult and neonatal mice. These results support the conclusion that this new approach is capable of generating a Th-type-1-biased, broad spectrum immune response, specifically at mucosal surfaces. The success of this design may provide a safe and effective vaccination alternative for human use

ISO-092 does not block diabetes induction in MAD rats.

<p>Male and female MAD (LEW.1WR1) rats (n=10/group) 21-25 days of age on Day -3 were induced for T1D with poly (I:C) on Days -3, -2, and -1 and infected with KRV on Day 1 (clear bar). ISO-092 or vehicle was administered via ALZET osmotic pump beginning of Day -1 (hashed bar). A positive control group was administered dexamethasone once daily by IP injection on Days 6-10 (checkered bar, <i>p</i> = 0.0006, vehicle vs. dexamethasone, Log-rank [Mantel-Cox] test).</p

DT22669 does not prevent diabetes in BBDP rats.

<p>Male BBDP rats (n=20-24/group) were administered DT22669 or vehicle by oral gavage beginning at 25 days of age until either 120 days of age or diabetes onset.</p

Aralast does not reverse diabetes in NOD mice, nor does it prevent diabetes in dysglycemic NOD mice.

<p>(<b>A</b>, <b>C</b>) Two independent (different cohorts of mice and different lots of reagents) studies were performed with non-diabetic female NOD mice with impaired glucose tolerance at 14 weeks of age (n=11-24/group) administered either 2 mg/mouse Aralast NP or saline on Days 1, 4, 7, 10, and 13. (<b>B</b>) Aralast NP did not improve fractional insulin area in A. (<b>D</b>) Mice in C that became diabetic continued to receive either Aralast NP saline and were implanted with an ALZET osmotic pumps administering 0.25 U/day insulin (dotted bar). Completion of the original dosing regimen did not lead to remission after cessation of insulin administration at approximately Day 21 post onset.</p