Method to Prevent Graft Rejection Using TGF-Beta to Induce T Suppressor Cells

Abstract

The invention relates to compositions and methods useful for preventing graft rejection in a recipient following organ transplantation.

Description

[0001]This application is a continuation of U.S. Ser. No. 10 / 772,768, filed Feb. 4, 2004, which is a continuation of U.S. Ser. No. 09 / 833,526, filed Apr. 11, 2001, which claims the benefit under 35 U.S.C. § 119(e) to application Ser. No. 60 / 196,446, filed Apr. 11, 2000, the disclosures of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The field of the invention is related to compositions and methods useful for preventing graft rejection in a recipient following organ transplantation.BACKGROUND OF THE INVENTION[0003]Organ transplantation has been used to improve the quality of human life. Substantial progress has been made in the transplantation of kidneys, hearts, lung, livers and pancreas. Current immunosuppressive drugs are generally effective in blocking the immediate rejection of these organs. However, when the organ is from an unrelated donor, i.e., allograft, these drugs become less successful with the passage of time because immunosup...

AI Technical Summary

Benefits of technology

The present invention provides methods for inducing T cell tolerance in solid organ transplant recipients. This is achieved by using compounds that inhibit or suppress immune function, such as anti-inflammatory cytokines, chemokines, prostaglandins, and nitric oxide. The invention also includes methods of inhibiting graft rejection by removing peripheral blood mononuclear cells from a donor and recipient, culturing them together in the presence of a compound that induces T cell suppressor activity, and administering these treated cells to the recipient after graft transplantation. The invention also uses closed systems for the purification, conditioning, and expansion of T cell populations before administering them to a patient.

Problems solved by technology

However, when the organ is from an unrelated donor, i.e., allograft, these drugs become less successful with the passage of time because immunosuppressive drugs are often ineffective in blocking chronic allograft rejection.

In addition, there are significant side effects associated with long term immunosuppressive therapy.

While the chances that the graft will function well for at least one year have been increasing, there has been a lack of progress in preventing chronic allograft rejection during the past 20 years (See FIG. 1; In Fundamental Immunology, 4th ed., Paul, W. E. (ed.

As a result, only 50% of transplants are still functioning years later.

Differences in MHC antigens between donor and recipient trigger a strong immune response by the recipient which results in the rejection of the transplanted organ.

Further studies have revealed additional participation of recipient antigen presenting cells, B cells, NK cells and NK T cells which adds complexity to the mechanisms responsible for graft rejection.

Unfortunately, the grafts may eventually fail weeks or months later.

Anti-donor antibodies have been claimed to promote chronic rejection, but this is controversial.

These drugs are associated with lifelong increased risks of infection and malignancy.

However, they have major side effects include serum sickness and infectious complications.

These monoclonal antibodies also have broad toxic side effects.

Unfortunately, large numbers of these cells are required for suppressive activity and their capacity to expand is very poor.

This strategy achieves central tolerance and should have long lasting effects, but has not yet been performed in large animals.

None of these strategies have been used to replace chronic therapy in clinical transplantation.

A major problem with strategies to block co-stimulatory molecules is that they cannot prevent generation of new T cells in the recipient capable of recognizing donor antigens.

Although CD4+ cells repeatedly activated in the presence of IL-10 develop potent suppressor activity, these cells have a very short life span and poor proliferative potential (Groux H, et al., (1997) Nature, 389:737-42).

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