Obstacles and opportunities for targeting the effector T cell response in type 1 diabetes

Abstract

Autoreactive lymphocytes display a programmed set of characteristic effector functions and phenotypic markers that, in combination with antigen-specific profiling, provide a detailed picture of the adaptive immune response in Type 1 diabetes (T1D). The CD4+ T cell effector compartment (referred to as “Teff” in this article) has been extensively analyzed, particularly because the HLA genes most strongly associated with T1D are MHC class II alleles that form restriction elements for CD4+ T cell recognition. This “guilt by association” can now be revisited in terms of specific immune mechanisms and specific forms of T cell recognition that are displayed by Teff found in subjects with T1D. In this review, we describe properties of Teff that correlate with T1D, and discuss several characteristics that advance our understanding of disease persistence and progression. Focusing on functional disease-associated immunological pathways within these Teff suggests a rationale for next-generation clinical trials with targeted interventions. Indeed, immune modulation therapies in T1D that do not address these properties of Teff are unlikely to achieve durable clinical response.

Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes

“…Collectively, these data suggest that immune profiles may identify candidates for such therapy, albeit validation in a larger cohort is clearly necessary. Further studies are needed to accurately determine if T cells are moving to a more anergic/senescent phenotype following ATG+G-CSF therapy, as has been observed with other T cell–targeting agents that have demonstrated clinical responses (21,22). …”

The complexity and diversity of major histocompatibility complex challenge disease association studies

“…Unregulated effector T‐cell expansion through failure in the control of regulatory T‐cell populations may in an inflammatory extracellular environment influence disease onset. Furthermore, the activation of the innate immune system through neutrophils, platelets, and complement system plays an important role in the development of the disease . Today, in addition to susceptibility loci in HLA, GWA studies have identified more than 60 loci associating with T1D mostly with small individual effect but together explaining most of the T1D heritability .…”

“…Furthermore, the activation of the innate immune system through neutrophils, platelets, and complement system plays an important role in the development of the disease. 79,80 Today, in addition to susceptibility loci in HLA, GWA studies have identified more than 60 loci associating with T1D mostly with small individual effect but together explaining most of the T1D heritability. 81 Combining candidate gene results with GWA risk SNPs may soon provide a genetic risk score to identify T1D patients.…”

Academic, Foundation, and Industry Collaboration in Finding New Therapies

“…38,39 Second, new immunomonitoring tools were developed to measure the ratio of effector T cells to regulatory T cells, which provided a new immune measurement to evaluate drug safety and mechanisms in future studies. 40 Third, several pharmaceutical companies and some academic centers expanded their research to develop safer versions of interleukin-2 (called interleukin-2 muteins), which are projected to have a larger margin of safety owing to selective targeting properties. 41 Fourth, the Immune Tolerance Network and Juvenile Diabetes Research Foundation established a preclinical research consortium, which developed a multicenter protocol for more robust validation testing in mice.…”