B-lymphocyte Targeting Therapies for Autoimmune Diabetes

描述（由申请人提供）：虽然1型糖尿病（T1D）最终是由自身反应性t细胞介导的，在NOD小鼠中，也可能在人类中，b淋巴细胞起着额外的关键致病作用。通过免疫球蛋白（Ig）介导的捕获摄取胰腺ss细胞蛋白的能力，b淋巴细胞似乎作为抗原提呈细胞（APC）亚群，最有效地支持糖尿病源性CD4 t细胞的扩增。最近的一项临床试验结果表明，CD20特异性利妥昔单抗抗体对b淋巴细胞的短暂消耗并不能长期减弱糖尿病源性自身免疫。我们最近发现用一种类似利妥昔单抗的CD20特异性抗体治疗不能有效预防

DESCRIPTION (provided by applicant): While type 1 diabetes (T1D) is ultimately mediated by autoreactive T-cells, in NOD mice, and also likely in humans, B-lymphocytes play an additional key pathogenic role. Through an ability to take up pancreatic ss cell proteins by immunoglobulin (Ig) mediated capture, B-lymphocytes appear to serve as an antigen presenting cell (APC) subset that most efficiently supports expansion of diabetogenic CD4 T-cells. Results from a recent clinical trial indicated transient depletion of B-lymphocytes with the CD20 specific rituximab antibody did not provide for long-term attenuation of diabetogenic autoimmunity. We recently found treatment with a rituximab- like CD20 specific antibody fails to efficiently prevent T1D development when initiated in NOD mice already manifesting signs of established high levels of pathogenic autoimmunity similar to that currently used to identify humans at high future disease risk. This appears to result from B-lymphocytes entering the pancreatic islets of NOD mice becoming CD20 negative. Furthermore, rituximab fails to deplete the marginal zone (MZ) subset of mature B-lymphocytes that can exert potent APC activity. We have also found diabetogenic clonotypes are enriched in the peritoneal CD20 negative B1 B-lymphocyte compartment of NOD mice. These issues call into question the extent that rituximab could be used as a mono-therapeutic T1D intervention approach. Thus, the overall goal of this proposal is to identify strategies that might independently, or in conjunction with rituximab, provide an improved B-lymphocyte directed T1D intervention approach. Aim 1 will address to what extent do diabetogenic B-lymphocytes reside in compartments refractive to anti-CD20 mediated deletion. A broader array of B-lymphocyte populations, including those in NOD islets, can potentially be deleted through use of agents inhibiting the BAFF/APRIL survival factors rather than anti-CD20. It has also been reported that in NOD mice the ability of B-lymphocytes to mediate expansion of diabetogenic T cells outpaces the capacity of other APC subtypes to support disease protective regulatory T-cell (Treg) responses. The FDA approved reagent GCSF (Neulasta) can enhance recruitment of myeloid dendritic cells with a capacity to support Treg activity. Hence, Aim 2 will evaluate whether BAFF/APRIL inhibition, rather than anti-CD20, provides a better means for B-lymphocyte directed late-stage T1D prevention in NOD mice, or if co-treatment with GCSF synergistically enhances the efficacy of either approach. Other preliminary studies indicate a currently unknown gene(s) within a T1D susceptibility locus designated Idd9/11 on Chromosome 4 contributes to disease pathogenesis in NOD mice by impairing an immunoregulatory pathway normally inhibiting autoreactive B-lymphocyte responses. We have evidence this pathway may be disrupted at other operational points by some human T1D susceptibility genes. Aim 3 is to determine if identification of a contributory Idd9/11 region gene(s) in NOD mice may reveal an immunoregulatory pathway, also potentially regulating diabetogenic B- lymphocyte development in humans, that may be amenable to pharmacological targeting.