Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2001-04-11
2004-07-06
Chan, Christina (Department: 1644)
Drug, bio-affecting and body treating compositions
Lymphokine
C424S085200, C424S093710, C435S007240, C435S070300
Reexamination Certificate
active
06759035
ABSTRACT:
FIELD OF THE INVENTION
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
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 immunosuppressive drugs are often ineffective in blocking chronic allograft rejection. In addition, there are significant side effects associated with long term immunosuppressive therapy. Each year approximately 10,000 kidney transplants are performed in the United States. 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.), Lippincott-Raven, Philadelphia, 1999, p. 1201). As a result, only 50% of transplants are still functioning years later. There is an urgent need, therefore, for new methods to prevent chronic rejection.
Graft rejection occurs when the immune system of the recipient recognizes foreign histocompatibility antigens. Infrequently, rejection is caused by antibodies, either preformed or the result of multiple blood transfusions. Rejection generally occurs when T lymphocytes from the recipient recognize and respond to donor histocompatibility antigens (Pescovitz M D, Thistlethwaite J R Jr, Auchincloss H Jr, et al. J Exp Med 1984;160:1495-1508).
There are two major histocompatibility complex (MHC) loci. Both major and minor histocompatibility antigens have been described as well as the genes that encode them. One encodes MHC class I antigens which are recognized by CD8+ T cells and another encodes MHG class II antigens which are recognized by CD4+ cells. MHC class I antigens are expressed on almost all tissues of the body. Both MHC I and II antigens are very polymorphic so that it is highly unlikely that antigens from unrelated individuals will be identical.
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. Foreign MHC antigens are directly recognized by the recipient's immune cells and also indirectly recognized by antigen-presenting cells of the recipient which have processed donor MHC antigens. The classical model of allograft rejection emphasizes CD4+ T cells of the recipient recognizing MHC class II antigens of the donor. These activated CD4+ cells serve as helper cells for recipient CD8+ which are sensitized by direct recognition of donor MHC class I antigens. The activated CD8+ cells then kill donor cells by lysing them (Mizuochi T, Golding H, Rosenberg A S, Glimcher L H, Malek T R, Singer A. J Exp Med 1985;162:427-443. 205). 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.
Graft destruction which occurs within the first few weeks after transplantation is called “acute rejection”. Usually, the use of immunosuppressive drugs temporarily prevents this result. Unfortunately, the grafts may eventually fail weeks or months later. This failure is referred to as “chronic rejection.” Both humoral and cellular mechanisms have been implicated in chronic rejection. Anti-donor antibodies have been claimed to promote chronic rejection, but this is controversial. It is generally believed that chronic rejection is the consequence of persistent sensitization of the immune system to donor MHC antigens. The immune cells of the recipients cannot “learn” to accept the donor MHC antigens as self and respond by attacking the graft.
There are two approaches to prevent graft rejection. The first is by treatment with non-specific immunosuppressants and the second is to induce donor-specific tolerance. The standard first approach is to use immunosuppressive drugs such as steroids, azathioprine, mycophenolate, cyclosporine, FK-506, rapamycin, leflunomide, or 15-deoxyspergualin. These drugs suppress immune responses by inhibiting lymphocyte gene transcription, cytokine signal transduction, nucleotide synthesis and cell differentiation. These drugs are associated with lifelong increased risks of infection and malignancy. In addition, anti-T cell antibodies such as anti-lymphocyte serum or anti-thymocyte globulin are also powerful immunosuppressants. However, they have major side effects include serum sickness and infectious complications More recently, OKT3, a mouse antibody directed against the CD3 antigen of humans, has become widely used in clinical transplantation. (Cosimi A B, Burton R C, Colvin R B, et al Transplantation 1981,32:535-539). Other monoclonal antibodies used include the antibody to the IL-2 receptor (anti-CD25) and the anti-ICAM-1 or anti-TNF-&agr; to block the effector mechanism of graft rejection. These monoclonal antibodies also have broad toxic side effects.
The ultimate goal of transplantation immunology is to enable the recipient to become tolerant to donor histocompatibility antigens. That is, to prevent the recipient's immune cells from recognizing donor antigens (i.e., accepting the donor organ as “self”) so that the graft is not rejected. The current state of the art in this area is reviewed herein and elsewhere (See Hugh Auchincloss, Jr., Megan Sykes, and David H. Sachs In Fundamental Immunology, 4th ed., Paul, W. E. (ed.), Lippincot-Raven, Philadelphia, N.Y., 1999 pp 1182-1222).
Tolerance can be achieved by three mechanisms. The first is “clonal deletion”; the elimination of lymphocytes which react to the donor antigens. The second is “clonal anergy”; the failure of T cells to proliferate in response to donor antigen. Anergy is generally reversible and can be reversed by infection or elimination of antigen (Rocha B, Tanchot C, Von Boehmer H. J Exp Med 1993;177:1517-1521) (Ramsdell F, Fowlkes B J. Science 1992;257:1130-1134). The third is “suppression”; which can be either non-specific or antigen-specific. Non-specific suppression can result from the secretion of soluble molecules that inhibit immune function. Suppressive molecules include prostaglandins (Snijdewint F G M, Kalinski P, Wierenga E A, Bos J D, Kapsenberg M I. J Immunol 1993;150:5321-5329, Betz M, Fox B S. J Immunol 1991;146:108-113), nitric oxide (Langrehr J M, Dull K E, Ochoa J B, et al. Transplantation 1992;53:632-640), and cytokines (Verbanac K M, Carver F M, Haisch C E, Thomas J M. Transplantation 1994;57:893-900); Raju G P, Belland S E, Eisen H J. Transplantation 1994;58:392-396).
Certain T cells, called “suppressor cells”, produce inhibitory cytokines which include IL-4, IL-10, and TGF-&bgr; which, non-specifically, block graft rejection (Qin L, Chavin K D, Ding Y, Woodward J E, Favaro J P, Lin J, Bromberg J S. Ann Surg 1994;220:508-519); (Qin L, Chavin K D, Ding Y, et al. J Immunol 1996; 156:2316-2323); (Zheng X X, Steele A W, Nickerson P W, Steurer W, Steiger J, Strom T B. J Immunol 1995;154:5590-5600). The existence of alloantigen-suppressor cells have been reported (Pearce N W, Spinelli A, Gurley K E, Hall B M. Transplantation 1993;55:374-379; Roser B J. Immunol Rev 1989; 107:179-202; Tomita Y, Mayumi H, Eto M, Nomoto K. J Immunol 1990;144: 463-473), but these cells are difficult to clone (Koide J, Engleman E G. J Immunol 1990;144:32-40).
Naturally occurring suppressor T cells produced by the thymus have been characterized in mice. These are CD4+ cells that express CD25, cell surface IL-2 receptor a chains (Shevach, E. A. (2000) Annu. Rev. Immunol. 18:423-449; Seddon, B., and D. Mason, (2000) 21.95-99; Sakaguchi, S., N. Sakaguchi, M. Asano, M. Itoh, and M.
Chan Christina
Dorsey & Whitney LLP
Huynh Phuong
Kosslak Renee M.
Silva Robin M.
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