Rationally designed small molecules to prevent type 1 diabetes

Abstract

Purpose of review: To review the recent findings that small 'drug-like' compounds block disease-specific HLA molecules in type 1 diabetes (T1D). Recent findings: The predominant genetic risk for developing T1D, the immune mediated form of diabetes, is conferred through human leukocyte antigen (HLA) genes. One such gene, termed HLA-DQ8, is present in 50-60% of patients with T1D and those at-risk. DQ8 presents diseaserelevant peptides to T cells, which mediate tissue specific destruction of pancreatic islets. Using a structure-based approach to evaluate the 'druggability' of the DQ8 molecule, methyldopa, a clinically well-established oral anti-hypertensive agent, was discovered to bind DQ8. Methyldopa blocked the activation of DQ8 specific T cells responding to self-antigens such as insulin but not influenza. In a proof-of-concept clinical trial (NCT01883804), methyldopa was administered to recent-onset T1D patients with the DQ8 gene that confirmed the mechanism of action and diminished inflammatory T cell responses towards insulin. Summary: Methyldopa blocks the diabetes-specific function of HLA-DQ8, which represents a personalized medicine approach to treat the underlying autoimmunity in T1D. Clinical trials are warranted and underway to evaluate methyldopa in potentially preserving residual beta-cell function in those with new-onset and at-risk for T1D.

MHC Class II Presentation in Autoimmunity

“…On the other hand, the basis of the thymic negative selection is directly linked with the MHC-IImediated presentation of self-antigens; therefore, balancing between central and peripheral tolerance versus autoreactivity may be caused by thermodynamic and kinetic peculiarities of the autoantigen loading on the MHC-II molecules. Elucidation of the molecular mechanisms underlying the assembly of the autoreactive trimolecular pMHC-II-TCR complexes and its further signaling may result in the elaboration of novel therapeutic modalities in terms of the induction of the immunological tolerance [46,[163][164][165], topological blockade of the self-antigens [166][167][168], and specific depletion of the autoreactive T cell clones [169,170].…”

Self-Antigens Targeted by Regulatory T Cells in Type 1 Diabetes

“…To improve clinical outcomes, islet antigen-specific Tregs, which are in very low frequencies in peripheral blood, may need to be selectively expanded prior to infusion. Another approach is to combine these Treg expanding therapies with agents that modulate effector T cell function, such as monoclonal antibodies targeting CD3 on T cells [ 15 , 74 , 75 , 76 , 77 ], CD2 on T cells [ 78 , 79 ], antithymocyte globulin [ 80 , 81 ], or potentially a small molecule inhibitor of effector T cells activated by the T1D-risk HLA-DQ8 molecule in T1D [ 82 , 83 , 84 ]. Ideally, the effector T cell response would be modulated or blocked first, which is followed by a Treg-inducing agent.…”

Novel approaches to the treatment of type 1 diabetes

“…A recent phase 1 trial in 20 HLA DQ8 positive persons with recent onset T1D showed that administration of methyldopa was associated with reduction in insulin-specific CD4+ T cells, with reduction in HbA1cwith C-peptide levels not declining. 6,7 The gut microbiome has been studied in a number of areas in medicine. Of interest, microbial fermentation of nondigestible carbohydrates can lead to production of several short chain fatty acids, including acetate, which is then taken up by pancreatic lymph nodes, where it appears to decrease autoreactive T cells as well as proinflammatory cytokines such as interleukin-21, and butyrate, which increases regulatory T-cell numbers, 8 with the potential to further reduce islet inflammation and apoptosis.…”

“…A small molecule, the antihypertensive agent methyldopa, blocks this binding. A recent phase 1 trial in 20 HLA DQ8 positive persons with recent onset T1D showed that administration of methyldopa was associated with reduction in insulin‐specific CD4+ T cells, with reduction in HbA1cwith C‐peptide levels not declining 6,7 …”