Fibroblast Compositions for Multiple Sclerosis Treatment
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Solution Overview
Problem
Current treatments for autoimmune diseases like multiple sclerosis are limited in effectiveness and often come with severe side effects, and there is a need for a specific and long-term solution to inhibit autoreactive T cells, particularly Th1-type T cells, to prevent disease progression.
Innovation Solution
Administering fibroblasts, which may be derived from various sources and treated to enhance their ability to suppress Th3 production of TGF-beta, to induce T regulatory cell activity and modulate the immune response, thereby correcting or ameliorating abnormalities associated with multiple sclerosis, such as abnormal cytokine levels and reduced stem cell proliferation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunosuppressive drugs (corticosteroids, cyclosporin A, FK506, rapamycin) are used to treat autoimmune diseases, then some symptoms can be alleviated, but serious side effects occur including nephrotoxicity, increased predisposition to infectious diseases, and enhanced incidence of neoplasia
Solution Approach 1:
The patent uses fibroblasts as intermediary cells that mediate immune modulation through contact with T cells. The fibroblasts express B7 molecules and other immunomodulatory surface molecules that interact with T cell receptors and co-stimulatory molecules, thereby suppressing autoreactive T cell activity without requiring conventional immunosuppressive drugs. This intermediary approach achieves therapeutic effectiveness while avoiding the harmful side effects of traditional pharmacological agents.
Solution Approach 2:
The fibroblasts are derived from the patient's own tissue (autologous), enabling the system to serve itself by using the patient's own cells to modulate their own immune response. This self-service approach eliminates the need for external pharmacological interventions and their associated side effects, while maintaining therapeutic effectiveness through the fibroblasts' inherent immunomodulatory capabilities.
2Reliability
If thymic tolerance mechanisms are used to prevent autoreactive T cells, then some auto-reactive T cells are eliminated, but autoreactive T cells reactive with self-antigens can still be found in the periphery
Solution Approach 1:
The fibroblasts are pre-treated to enhance their ability to suppress Th3 production of TGF-beta and to express high levels of B7 molecules and other immunomodulatory surface molecules before administration. This preliminary preparation ensures that when the fibroblasts contact autoreactive T cells in the periphery, they can immediately and effectively suppress T cell activity, thereby achieving more complete tolerance induction than conventional thymic mechanisms alone.
Solution Approach 2:
The patent modifies the functional parameters of fibroblasts through treatment protocols that enhance their immunomodulatory capacity. Specifically, the fibroblasts are treated to increase expression of B7 molecules, increase suppressive activity against Th3 cells, and enhance production of immunomodulatory cytokines. These parameter changes enable the fibroblasts to achieve more effective and complete suppression of autoreactive T cells compared to untreated fibroblasts or conventional tolerance mechanisms.
3Reliability
If DNA vaccines encoding autoantigens are administered to anergize autoreactive T cells, then tolerizing effects are achieved, but the success hinges on co-administration of Th2-associated cytokines which complicates the treatment protocol
Solution Approach 1:
The patent merges multiple immunomodulatory functions into a single fibroblast cell product. The fibroblasts simultaneously express B7 molecules for T cell suppression, produce immunomodulatory cytokines including IL-10 and TGF-beta, and provide contact-mediated inhibition of autoreactive T cells. This merging of functions into a single therapeutic agent achieves tolerizing effects without requiring the complex co-administration protocols needed for DNA vaccines combined with cytokines.
Solution Approach 2:
The fibroblasts serve multiple functions simultaneously: they provide contact-mediated inhibition of T cells, produce immunomodulatory cytokines (IL-10, TGF-beta), express B7 molecules for co-stimulatory inhibition, and promote regenerative processes. This multi-functionality consolidates what would otherwise require multiple separate therapeutic agents and administration protocols into a single universal treatment product, thereby achieving tolerizing effects with simplified protocol.
Data Source
AI summary
Described are means, methods, and compositions useful for treatment of multiple sclerosis through the utilization of fibroblasts and/or derivatives thereof to concurrently stimulate regenerative processes while inducing a protolerogenic immune modulatory program. In certain embodiments, fibroblasts are selected for the concurrent properties of immune modulation and regeneration by enrichment for CD73 expressing fibroblasts. In particular embodiments, stimulation of regeneration implies activation of endogenous neural progenitor cells. In some embodiments, stimulation of regeneration implies induction of remyelination. The utilization of fibroblasts as a superior source for immune modulation, prevention of immune mediated pathology, and activation of T regulatory cells is provided within the context of multiple sclerosis.