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

[0034]This strategy is unlike almost all other treatment therapies currently in use because cells, rather than organ recipient as a whole, are treated with potent pharmacologic agents. Thus, the recipient is spared from the severe side effects associated with these agents. An advantage of the present invention is that it may reduce or minimize the need to administer highly toxic immunosuppressive medicines that must be given to recipients of organ transplants. In the present invention, the recipient's own immune cells are induced to suppress the immune response, thus, the doses of toxic immunosuppressive drugs administered for this purpose can be reduced.

[0035]Thus, the present invention provides a lowered probability of serious side effects as only trace amounts of compounds which may block the immune response are returned to the recipient.

[0036]The present invention shows that a population of a recipient's T cells can be induced to block an immune attack against the donor organ. Without being bound by theory, it appears that there are several ways the methods of the invention may work, either alone or in combination. First, recipient cells may be activated to become tolerant to the donor cells. Second, recipient cells may be activated to assume a surveillance role and prevent other recipient cells from killing donor cells. Third, treatment of recipient cells with a suppressive compound may inhibit the cytotoxic activity of some recipient T cells by inducing other recipient cells to have suppressor activity. For example, in FIGS. 2-4, TGF-β is used to induce various T cell subsets to have suppressor activity and prevent lysis of donor cells. Suppressing the lysis of donor cells by recipient cells will decrease or eliminate chronic graft rejection.

[0037]Accordingly, the present provides compositions and methods of inducing T cell tolerance in an organ transplant recipient. The present invention provides methods comprising removing peripheral blood mononuclear cells (PBMCs) from both a recipient and a donor, mixing the recipient and donor cells together, and treating the cells with a regulatory composition to generate a population of suppressor T cells. These suppressor T cells can be introduced into a recipient at the time of transplant, or at various times thereafter to prevent chronic graft rejection.

[0038]By “recipient” herein is meant a human which is to receive an organ transplant. In some case, the recipient may be an animal, including but not limited to rodents including mice, rats, and hamsters, domestic animals, wild animals and primates. Likewise, for the purpose of the invention, a “donor” is a human or animal from which the organ is obtained.

[0039]The present invention is directed to methods utilized in organ transplant. By “organ” herein is meant solid organs such as kidneys, heart, lungs, liver, and pancreas.

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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