Title:  Specific immune system modulation

United States Patent:  6,355,238

Assignee:  Yale University (New Haven, CT)

Filed:  March 21, 1997

Methods and pharmaceutical compositions for modifying the immune response of a mammal to a specific antigen are provided. The methods include treating an antigen presenting cell to enhance expression of a major histocompatibility complex molecule and reacting the treated antigen presenting cell with the antigen extracorporeally to form an antigen-associated antigen presenting cell.

SUMMARY OF THE INVENTION

The present invention provides methods and pharmaceutical compositions for specifically modifying an immune system response to an antigen. In particular, the invention provides methods and compositions for actively immunizing patients against malignant cells or lymphocytes responsible for autoimmune disease. Also provided are methods for inducing immunologic tolerance to autologous or exogenous antigens and compositions useful in suppressing clinically undesirable immunologic reactions.

According to one aspect of the invention, a method for forming an antigen-associated antigen presenting cell is provided. The method comprises treating a preparation containing an antigen presenting cell to enhance expression by the cell of a major histocompatibility complex molecule and reacting the treated antigen presenting cell with the antigen extracorporeally to form an antigen-associated antigen presenting cell. In a preferred embodiment, the antigen presenting cells are T cells which have been treated to enhance expression of the major histocompatibility complex class I molecules and the antigens are peptides. The peptide antigens are associated with a solid tumor malignancy, an immunodeficiency disease or a hypersensitivity disease.

A preferred method for enhancing expression of the major histocompatibility complex molecules is by subjecting the preparation containing the antigen presenting cells to room temperature. Alternate methods of treatment of the antigen presenting cells also are provided.

According to another aspect of the invention, a method for making a pharmaceutical preparation for administration to a mammal is provided. The method comprises placing the above-described antigen-associated antigen presenting cell, or components of same, in a pharmaceutically acceptable carrier.

According to yet another aspect of the invention, a method for specifically modifying the immune system response of a mammal to an antigen is provided. The method comprises administering the above-described pharmaceutical preparation to the mammal. In a preferred embodiment, the antigen presenting cells are isolated from a human recipient, treated and returned to the patient Pin the form of antigen-associated antigen presenting cells. Optionally, the pharmaceutical preparation is stored in aliquots containing an amount of antigen-associated antigen presenting cells sufficient to boost the immune response of the patient. Selection of an amount of cells necessary to boost the patient's immune response is within the capabilities of those skilled in the art without the need for undue experimentation. The amount of cells is, in part, dependent upon the patient's age, weight and medical profile. Preferably, an amount of cells ranging from a minimum of about 25,000 to a maximum of about 200x10⁶ antigen presenting cells is sufficient to boost the immune response of the patient (Ben-Nun, A., et al., "Vaccination against autoimmune encephalomyelitis with T lymphocyte line cells reactive against myelin basic protein", Nature 292:60-61 (1981); Holoshitz, J., et al., "Lines of T lymphocytes induce or vaccinate against autoimmune arthritis", Science 219:56-58 (1983); Lider, O., et al., "Anti-idiotypic network induced by T cell vaccination against experimental autoimmune encephalomyelitis", Science 239:181-183 (1988); Khavari, P., et al., "Specific vaccination against photoinactivated cloned T cells", Abstract Clin. Res. 36:662A (1988); and Edelson, R., et al. "Treatment of cutaneous T cell lymphoma by extracorporeal photochemotherapy", N. Engl. J. Med. 316:297-303 (1987).

In one embodiment, treatment of the antigen presenting cells to enhance expression of the major histocompatibility complex molecules comprises irradiating the antigen presenting cells in the presence of a photoactivatable agent. In some instances, the photoactivatable agent may be administered orally to the patient prior to the enhancement step.

According to still another aspect of the invention, a pharmaceutical composition for modifying an immune system response to an antigen is provided. The composition comprises a pharmaceutically acceptable carrier and a plurality of antigen presenting cells, each cell having on its surface a major histocompatibility complex molecule associated with an antigen. In a preferred embodiment, the plurality of major histocompatibility complex molecules represent a relatively homogeneous population. The antigen presenting cells of the present invention have an elevated concentration of major histocompatibility molecules compared to corresponding, naturally occurring antigen presenting cells. The preparation contains an amount of antigen presenting cells sufficient to modify the patient's immune system response. Selection of an amount of cells necessary to modify the patient's immune response is within the capabilities of those skilled in the art without the need for undue experimentation. The amount of cells is, in part, dependent upon the patient's age, weight and medical profile. Preferably, an amount of cells ranging from a minimum of about 25,000 to a maximum of about 200x10⁶ antigen presenting cells is sufficient to boost the immune response of the patient. (Ben-Nun, A., et al., supra.; Holoshitz, J., et al., supra.; Lider, O., et al., supra.; Khavari, P., et al., supra.; and Edelson, R., et al., N. Engl. J. Med. 316, supra.

Claim 1 of 8 Claims

What is claimed is:

1. A pharmaceutical composition for down-regulating an immune system response to an antigen, comprising:

a preparation containing a mixture of antigen-associated antigen presenting cells and beta-2 microglobulin, wherein the antigen-associated antigen presenting cells have an increased number of antigen-bound major histocompatibility complex molecules on their surfaces as compared to cells withdrawn from a mammal, the preparation containing a concentration of antigen presenting cells sufficient to down-regulate an immune system response and an amount of beta-2 microglobulin greater than the concentration of beta-2 microglobulin that would be found in vivo; and

a pharmaceutically acceptable carrier.

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