Drug – bio-affecting and body treating compositions – Lymphokine
Patent
1997-01-21
2000-06-13
Saunders, David
Drug, bio-affecting and body treating compositions
Lymphokine
424 852, 4241851, A61K 4500, A61K 3900
Patent
active
060746351
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to an antigen independent method for the activation of T cells. The invention also relates to a method for increasing lymphokine production in a T cell culture and a method for increasing the immune response at specific sites in vivo which has therapeutic applications in the treatment of disease.
BACKGROUND OF THE INVENTION
T cells are involved in the immune response and are primarily involved in cellular immunity, such as guarding against virally infected cells, fungi, parasites and foreign tissue.
Briefly, T cells are activated by binding to antigen-displaying macrophages. However, the T cell receptor must specifically complex with the antigen and a Major Histocompatibility Complex (MHC) protein displayed on the surface of the macrophage.
The binding induces the macrophage to release interleukin-1, a polypeptide growth factor, which stimulates the bound T cell to proliferate and differentiate. This proliferation and differentiation is enhanced by the T cells autostimulatory secretion interleukin-2. The T cell can differentiate into a number of different phenotypes, such as cytotoxic T cells which are specifically targeted to antigen displaying host cells and are capable of lysing the cell, helper T cells which are involved in activating cytotoxic T cells and in co-operating with B cells to produce antibodies and memory T cells which upon re-encountering their cognate antigen proliferate at a faster rate than non-memory T cells.
It will be apparent to one skilled in the art that the activation of T cells is an important step in the immunological response. By manipulating the activation of T cells it will be possible to obtain useful immunological products and develop more efficient treatment techniques.
Previously, to achieve T cell activation, a macrophage displaying an antigen and an MHC protein was required. A number of problems and drawbacks are associated with this, a major drawback being that only T cells specific for the antigen are activated. Other T cells not specific for the antigen remain unactivated. Other problems may arise if the desired antigen is difficult to obtain or hazardous to work with. Additionally, if an antigen is used in cell culture to achieve activation and it is not easy to remove, contamination problems may occur.
The same problems will occur in vivo and it is obviously undesirable to infect an individual with an antigenic substance.
By achieving antigen independent T cell activation it will be possible to activate a population of T cells without the need to isolate and display an antigen on the surface of a macrophage.
It is known that interleukin-2 is potent T-lymphocyte growth enhancer and the use of interleukin-2 as an adjuvant has been described. In this role interleukin-2 was thought to function as an expander of the population of already activated T-lymphocytes. However, it was not known that interleukin-2 (in combination with other cytokines) could act specifically to activate T-lymphocytes in an antigen independent manner.
SUMMARY OF THE INVENTION
According to the present invention there is provided a method for antigen independent activation of T cells comprising contacting T cells with a combination of cytokines.
Preferably, the T cells are contacted with at least two of the following:
The T cells may be naive T cells and/or memory resting T cells, most suitably naive CD45RA.sup.+ cells and/or memory resting CD45RO.sup.+ cells.
Suitably, the concentration of interleukin-2 is from 100 to 400 U/ml, the concentration of interleukin-6 is from 400 to 600 U/ml and the concentration of tumour necrosis factor .alpha. is from 15 to 35 ng/ml. More preferably, the concentration of interleukin-2 is from 200 to 300 U/ml, the concentration of interleukin-6 is about 500 U/ml and the concentration of tumour necrosis factor .alpha. is about 25 ng/ml.
The T cells may be activated in vitro, for example, in a method for obtaining increased lymphokine production from a T cell culture, comprising activating the T cells accordin
REFERENCES:
patent: 4879111 (1989-11-01), Chong
patent: 5091511 (1992-02-01), Sone et al.
patent: 5425940 (1995-06-01), Zimmerman et al.
J. Bryne et al., "Differential Activation Requirements For Virgin and Memory T Cell", J. Immunol. (1988) 141(10):3249-3257.
S. Carding et al., "Activation of Cytokine Genes in T Cells during Primary and Secondary Murine Influenza Pneumonia", J. Exp. Med. (1993) 177:475-482.
A. Chinn et al., "T Cell Proliferative Response to Interleukin 2: Different Frequency of Responders Among CD45RO and CD45RA Subsets", Cellular Immunology (1990) 131(1):132-139.
N. Damle et al., "Distinct Regulatory Effects of IL-4 and TNF-.alpha. During CD3-Dependent and CD3-Independent Initiation of Human T-Cell Activation", Lymphokine Research (1989) 8(2):85-97.
J. Depper et al., "Interleukin 2 (IL-2) Augments Transcription of the IL-2 Receptor Gene", Proc. Natl. Acad. Sci. USA (1985) 82:4230-4234.
J. Farrar et al., "Thymoma Production of T Cell Growth Factor (Interleukin 2)", J. Immunol. (1980) 125(6):2555-2558.
R. Garman et al., "B-Cell-Stimulatory Factor 2 (.beta.2 Interferon) Functions as a Second Signal for Interleukin 2 Production by Mature Marine T Cells", Proc. Natl. Acad. Sci. USA (1987) 8:7629-7633.
D. Gray, "Immunological Memory: A Function of Antigen Persistance", Trends in Microbiology (1993) 1(2):39-42.
Z. Grossman et al., "Adaptive Cellular Interactions in the Immune System: The Tunable Activation Threshold and the Significance of Subthreshold Responses", Proc. Natl. Acad. Sci. USA (1992) 89:10365-10369.
K. Horgan et al., "Hyporesponsiveness of "Naive" (CD45RA+) Human T Cells to Multiple Receptor-Mediated Stimuli but Augmentation of Responses by Co-Stimuli", Eur. J. Immunol. (1990) 20:1111-1118.
I. Lefkovits et al., "Limiting Dilution Analysis of the Cells of Immune System I. The Clonal Basis of the Immune Response", Immunology Today (1984) 5(9):265-268.
M. Minutello et al., "Compartmentalization of T Lymphocytes to the Site of Disease: Intrahepatic CD4+ T Cells Specific for the Protein NS4 of Hepatitis C Virus in Patients with Chronic Hepatitis C", J. Exp. Med. (1993) 178:17-25.
M. Ostensen et al., "Tumor Necrosis Factor-.alpha. Enhances Cytolytic Activity of Human Natural Killer Cells", J. Immunol. (1987) 138(12):4185-4191.
L. Owen-Schaub et al., "Regulation of Lymphocyte Tumor Necrosis Factor Receptors by IL-2" J. Immunol. (1989) 143(7):2236-2241.
W. Paul, "Fundamental Immunology, 3.sup.rd Edition Raven Press, New York", (1993) pp. 766-768, 807-815, 966-970.
S. Romagnani et al., "Cytokines: Basic Principles and Practical Applications", Challenges Mod. Med. (1994) 8:49-52.
S. Rosenberg et al., "Observations on the Systemic Administration of Autologous Lymphokine-Activated Killer Cells and Recombinant Interleukin-2 to Patients with Metastatic Cancer", The New England Journal of Medicine (1985) 313(23):1485-1486.
P. Scheurich et al., "Immunoregulatory Activity of Recombinant Human Tumor Necrosis Factor (TNF)-.alpha.: Induction of TNF Receptors on Human T Cells and TNF-.alpha.-Mediated Enhancement of T Cell Responses", J. Immunol. (1987) 138(6):1786-1790.
I. Schmid et al., "A Gentle Fixation and Permeabilization Method for Combined Cell Surface and Intracellular Staining With Improved Precision in DNA Quantification", Cytometry (1991) 12:279-285.
J. Sleasman et al., "The Role of Functionally Distinct Helper T Lymphocyte Subpopulations in the Induction of Human B Cell Differentiation", Eur. J. Immunol. (1990) 20:1357-1366.
K. Smith, "Lowest Dose Interleukin-2 Immunotherapy", Blood (1993) 81(6):1414-1423.
H. Teh et al., "Activation of Nonspecific Killer Cells by Interleukin 2-Containing Supernatants", J. Immunol. (1983) 131(4):1827-1833.
R. Testi et al., "LEU 23 Induction as an Early Marker of Functional CD3/T Cell Antigen Receptor Triggering Requirement for Receptor Cross-Linking, Prolonged Elevation of Intracellular [Ca++] and Stimulation of Protein Kinase C", J. Immunol. (1989) 142(6):1854-1860.
M. Tsudo et at., "Characterization of th
Blackburn Robert P.
Chiron Corporation
Harbin Alisa A.
Saunders David
Trujillo Doreen Y.
LandOfFree
T cell activation does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with T cell activation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and T cell activation will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2066165