Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1994-05-31
1998-05-05
Ulm, John
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
4352523, 4353201, 530350, 536 234, C07K 14715, C07K 1900, C12N 1562
Patent
active
057472920
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to the field of immunotherapy, more specifically to the introduction of genetic material encoding chimeric cytokine receptors into lymphocytes to reduce the dependency of the activated lymphocytes on T helper cells and/or growth factors supplied by T.sub.H -cells.
BACKGROUND
T lymphocytes are responsible primarily for protection against intracellular pathogens and malignant tumors. Individuals who are grossly deficient in T-cell immunity frequently succumb to overwhelming infections by organisms such as cytomegalovirus, Pneumocystis carinii, Candida, and other apparently "opportunistic" pathogens, including bacteria, viruses and fungi. Immunosuppression can result from a variety of causes, including viral infections (for example, with the HIV virus), as a result of chemical therapy, and malignancies (particularly of types that affect the hematopoietic system). T-cell immunity is also the major mechanism for rejection of allogeneic tissue or organ transplants. In fact, a major limitation to transplant therapy has been the difficulty in suppressing T-cell allograft rejection reactions without overly compromising vital protective mechanisms.
The adoptive transfer of antigen (Ag)-specific T cells to establish immunity appears to be an effective therapy for some viral infections and tumors in the mouse animal model system. (For a review, See P. D. Greenberg, in Advances in Immunology F. Dixon Ed. Academic Press, Inc. Orlando Fla. (1991), pp. 280-355.) However, the efficacy of an adoptive transfer method is dependent upon many factors, including the longevity of the transferred clones and the lack of toxicity to the host of the transferred cells.
Mature T lymphocytes generally express the CD3 cell surface molecule, but consist predominantly of two basic subtypes based on their mutually exclusive expression of cell surface molecules CD4 and CD8. CD4.sup.+ T cells are generally involved in "helper" functions in immune responses and secrete cytokine molecules, in particular interleukin 2 (IL-2), upon which the cytotoxic CD8.sup.+ T cells are dependent. CD4.sup.+ T cells are often referred to as T helper (T.sub.H) cells. CD8.sup.+ cells are involved in "effector" functions in immune responses, such as direct cytotoxic destruction of target cells bearing foreign antigens, and represent an important mechanism for resistance to viral infections and tumors. The functional distinction between CD4.sup.+ and CD8.sup.+ T cells is based on the ability of CD4.sup.+ cells to recognize antigen presented in association with class II MHC molecules, and CD8.sup.+ cells to recognize antigen presented in association with class I MHC molecules. The CD8.sup.+ cells that mediate this lytic function are designated cytotoxic T lymphocytes (CTLs). Although most CTL are of the CD8.sup.+ phenotype, some CTL of the CD4.sup.+ phenotype have been described. Generally, individual CTLs (whether CD8.sup.+ or CD4.sup.+) are antigen-specific.
Lymphocytes are dependent upon a number of cytokines for proliferation. For example, CTLs are dependent on helper T (T.sub.H) cell-derived cytokines, such as IL-2, for growth and proliferation in response to foreign antigens. (Zinkernagel and Doherty, Adv. Immunol. 27:51, 1979; Male et al., Advanced Immunology, Chap. 7, Gower Publ., London, 1987; Jacobson et al., J. Immunol. 133:754, 1984). IL-2, for example, is a potent mitogen for cytotoxic T lymphocytes (Gillis and Smith,. Nature 268:154, 1977), and the combination of antigen and IL-2 causes proliferation of primary CD8.sup.+ T cells in vitro. The importance of IL-2 for the growth and maintenance of the CD8.sup.+ CTL in vivo has been documented in models of adoptive immunotherapy in which the therapeutic efficacy of transferred anti-retroviral CD8.sup.+ cells is enhanced by subsequent administration of IL-2 (Cheever et al., J. Exp. Med. 155:968, 1982; Reddehase et al., J. Virol. 61:3102, 1987). IL4 and IL-7 are also capable of stimulating the proliferation of at least a sub-population of mature CD8.sup.+ CTL (Alders
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Boshart et
Greenberg Philip D.
Nelson Brad H.
Fred Hutchinson Cancer Research Center
Ulm John
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