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New therapeutic pathway for autoimmune and inflammatory disorders

A recently-discovered class of T cells - T follicular regulatory (TFR) cells - controls the production of antibodies. TFR cells inhibit T follicular helper (TFH) cells, which mediate antibody production in lymph nodes. Several autoimmune diseases are caused by inappropriate antibodies, including lupus and myasthenia gravis, and accordingly TFH cells are up regulated in these diseases. However, until now there has been no way of controlling the production of antibodies to specific antigens through T cell regulatory pathways. The Sharpe Laboratory has found a target on TFR cells (the surface receptor PD-1 and its ligand PD-L1) that when suppressed, increases the number of TFR cells, which they show selectively reduces antibody levels in vivo (HU Case 3723). They have also shown that transplanting populations of TFR can cause similar effects. Most importantly, they have shown that TFR cells selectively suppress humoral immune responses, but do not inhibit other arms of the immune system.

TFR cells circulate in the blood, home to lymph nodes, and inhibit antibody production there. The Sharpe Lab has found for the first time that TFR cells circulate in the blood of mice, move to the germinal centers in lymph nodes, and inhibit the antibody-producing B cell response there. They transferred blood TFR cells from mice challenged with an antigen into mice completely lacking their own TFR cells. In the recipient mice, the transferred TFR cells not only move from the blood to the lymph nodes, but potently inhibit the production of IgG specific to the antigen challenge in the donor.

Intellectual Property Status: Patent(s) Pending

Applications

Antibodies can be specifically suppressed to treat autoimmune disease
Current treatments for autoimmune disease (e.g., corticosteroid therapy) are generalized and have multiple undesirable side effects. This invention has the potential to revolutionize treatment of these autoimmune diseases by specifically inhibiting the part of the immune response causing the disease while avoiding effects on other arms of the immune system. Diseases arising from antibodies to self proteins (auto-antibodies) such as myasthenia gravis and recurrent forms of Graves’ disease are particularly good candidates for this therapy, as well as other autoimmune diseases with humoral immune components such as lupus, multiple sclerosis, graft-vs.-host-disease, rheumatoid arthritis, autoimmune hepatitis, and juvenile dermatomyositis.

Amplified TFR populations can be transplanted to target specific antibodies
TFR cells can be amplified in culture and transplanted to patients to suppress antibody production. They can be used in personalized therapy by extracting them from patients, selecting those that mediate the specific autoimmune response, amplifying and resupplying them to the patient.

Antibodies to specific therapeutic proteins can be suppressed or enhanced
A major complication in gene therapy is antibodies against the gene product being replaced. And in hemophilia, 25% of patients develop antibodies to platelet proteins during replacement therapy. This invention can be used to specifically suppress those responses.

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