Potentiation of the immune response

Abstract

A method for stimulating proliferation of T-cells containing cytoplasmic post-prolyl dipeptidase activity; the method, in one aspect, involves contacting the T-cells with an organic compound at a concentration below 10−8M, wherein the compound is characterized in that: (a) it is capable of crossing the membrane of T-cells to enter the cytoplasm, (b) it binds to the dipeptidase activity at a concentration of below 10−8M, and thus (c) stimulates proliferation of the T-cells at that concentration.

Description

RELATED APPLICATIONS [0001] This application is a continuation and claims priority under 35 U.S.C. § 120 to application U.S. Ser. No. 09 / 491,855, filed January 26, entitled, “Potentiation of the Immune Response,” pending, which is a divisional application and claims priority under 35 U.S.C. § 120 to U.S. Ser. No. 08 / 852,395, filed May 7, 1997, entitled “Potentiation of the Immune Response,” now issued as U.S. Pat. No. 6,040,145, the entire contents of each of which are incorporated herein by reference.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0002] This invention was made with Government support under NIH grant No. AI36696, and the Government therefore has certain rights in this invention.BACKGROUND OF THE INVENTION [0003] This invention relates to treatment of viral infections using organic compounds which interact with T-cell enzymes. [0004] One of the classic markers of full-blown AIDS resulting from long-term infection with HIV-1 is a severe depletion of CD4+ T-cells, which ...

AI Technical Summary

Benefits of technology

[0005] We have discovered that the activation state of human T-cells can be affected by compounds which interact with a cytoplasmic post-prolyl dipeptidase activity which has similarities to, but is distinct from, the membrane-bound T-cell serine protease CD26. The compounds useful in the invention are inhibitors of this activity, which is, in naturally-occurring T-cells in healthy individuals, involved in protection of T-cells from apoptosis, or programmed cell death. Thus, in high concentrations, the inhibitors hasten the death of T-cells, by inhibiting the protective enzyme. We have discovered, surprisingly, that at low concentrations the inhibitors exhibit a paradoxical effect: they are potent stimulators of T-cell activity in HIV-infected individuals. The concentrations of inhibitor which induce this T-cell stimulatory response at very low (on the order of 10−8-10−12M), and therefore the inhibitors can be used with minimal side effects, even if, in larger doses, the inhibitors would be toxic.

[0009] We believe that administration of low concentrations of the inhibitors of the invention may have an allosteric effect such that the T-cell cytoplasmic enzyme, which is a multimeric (i.e., multiple subunit) enzyme, exhibits an increased affinity of the enzyme for its natural substrate or ligands, allowing the previously blocked T-cell to proceed to full activation, and hence survival, proliferation, and interleukin-2 production. Stimulation of the T-cell immune response in HIV-infected patients according to the invention yields increased numbers of immune effector cells, which can fight both HP, itself and other opportunistic pathogens.

[0010] Treatment according to the invention has the advantages of specificity and low toxicity, not just because of the low concentrations of inhibitor which can be used, but also because, in T-cells of patients not infected with a virus such as HIV, the inhibitors have no discernable effect. Furthermore, treatment according to the invention advantageously does not necessarily require in vitro manipulation of the T-cells from HIV-infected patients. Furthermore, no immunization is required, and treatment will be effective even where HIV proteins have mutated because the therapy targets a cellular enzyme. The fact that, in T-cells treated according to the invention in vitro, no increase in the level of the HIV protein p24 is observed, probably indicates that the T-cells which are infected with HIV are not stimulated by the low dose inhibitor treatment of the invention.

[0013] The low dose administration of inhibitors of the invention can also be used to produce an adjuvant effect in HIV-negative individuals, who are to be immunized with peptides or other viral antigens; this mode of vaccination can be used for prophylaxis for HIV, as well as any other viral pathogen. Ordinarily, meaningful cytolytic T-lymphocyte (“CTL”) responses, both in vitro and in vivo, have been difficult to achieve with peptide immunization. The invention should make it possible to produce significant CTL responses to viral peptides, e.g., peptides from influenza, HIV, human papilloma virus, and herpes peptides. This adjuvant effect can also be used to stimulate CTL responses to peptide antigens from other pathogens as well, e.g., pathogenic bacteria such as toxigenic E. coli, and protozoan pathogens such as the pathogens which are the causative agents of malaria and amoebic dysentery. The compounds, when used as adjuvants, are preferably administered orally.

[0014] The invention provides a new and highly advantageous method of potentiating the immune response in both HIV infected and uninfected patients, in methods employing extremely low concentrations of inhibitors which, at these concentrations, exhibit a paradoxical effect (i.e., they act as stimulatory rather than inhibitory molecules, as they would at higher concentrations). The very low concentrations employed according to the invention allows treatment with minimal side reactions and toxicity. The specificity of the treatment of the invention also avoids such adverse effects, which are seen, for example, in treatment with immune stimulatory compounds such as interleukin-2.

Problems solved by technology

We believe that this blocking of activation, involving this cytoplasmic activity, prevents differentiation of T-cells of HIV-infected individuals into effector cells, eventually leading to T-cell death.

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