Selective Thymic Glucocorticoid Receptor Modulation by Giving Pro-Drug Thymosine α-1 Immuno-Modulator in Chronic Level of Glucocorticoids Exposure Thus Preventing Autoreactive T Cells Production and Establishing Central Tolerance

Abstract

Sourav Singla, Kartikey Sringari, Yogesh Khaleri, Prisha Sharma, Mandeep Singh and Jasimar Kaur

Background: We developing a pro-drug to protect the thymus against the atrophy caused by chronic glucocorticoids level in body and suppress production of auto reactive T cell from thymus without inhibiting normal T cell proliferation and thus prevent autoimmune disorder and delay various stages of autoimmunity.

Conceptual Innovation and Scientific Rationale: Re-engineering thymosin α-1 as a pro drug that protects T cell from chronic glucocorticoid levels. Thymosin α-1 potentiates T cell mediated immune response via differentiation and maturation of T cell progenitor cells3. Vamorolone (VBP 15) shows potent inhibition of pro inflammatory NF-kB(Nuclear Factor kappa light chain enhancer of activated B cells) pathways via high-affinity binding to the glucocorticoid receptor4.

Proposed Concept and Methodology: Create a pro drug by chemically conjugating thymosin α-1 peptide to a known SEGRM Vamorolone via a cleavable linker, where in thymus by cleaving through thymus specific serine protease it release thymosin α-1 which exerts its direct anti-apoptotic and immunomodulatory effects on thymocytes and simultaneously localized SEGRM Vamorolone modulates the glucocorticoid receptors to protect the stromal microenvironment from chronic glucocorticoids level and reduce inappropriate thymocytes death.

Conclusion and Healthcare Implications: Re-engineer Thymosin α-1 Pro drug thus helps thymocytes to build resistance from chronic high glucocorticoids level in body and maintain central tolerance without suppressing normal T cell proliferation. By protecting the thymus’s ability to enforce central tolerance, this strategy aims to prevent the initial emergence of pathogenic autoreactive T cells and thus prevent auto-immune disorders.

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