Seattle Treatment Education Project (STEP) Perspective, Vol. 7, No. 1 - Spring 1995; A Publication of the Seattle Treat- ment Education Project, 127 Broadway E. Ste. 200, Seattle, WA 98102 * (206) 329-4857. Published 3 times a year
Paul A. Linnemeyer

Interleukin-2

IL-2 is secreted by a subset of CD4+ T helper cells known as Th1 cells. Th1 cells secrete the cytokines IL-2 and gamma-interferon, both of which have pronounced stimulatory effects on cell-mediated immunity. In contrast, another T helper cell subset, Th2, secretes cytokines whose main effects are on the regulation of the production of antibodies (humoral immunity). It has been postulated that maintaining a balance between cell-mediated immunity and humoral immunity is important for the appropriate regulation of the immune system. Some researchers believe that in HIV-positive individuals, AIDS-related disease progression ensues when Th2-responses (production of IL-4, IL-5, IL-6, IL-10) become dominant over Th1 responses (production of IL-2 and gamma-interferon)[4] . Although this theory is debatable, it is likely that the lack of IL-2 production underlies the loss of immune responses in AIDS. HIV-positive individuals with decreased numbers of CD4+ T cells produce less IL-2 in vivo[5] and their white blood cells produce less IL-2 in vitro after antigenic challenge[6] . Furthermore, the loss of functional CD4+ T cells and decreased production of IL-2 are highly correlated with disease progression in AIDS.[6] Moreover, an abundance of data support the conviction that IL-2 is important and required in the mounting of a successful cell-mediated immune response.[2]

IL-2 is a desirable therapeutic agent in the treatment of AIDS-related immune suppression because it stimulates the proliferation and cytotoxic activation of CD8+ antigen-specific T cells and NK cells. This results in enhanced antiviral activity and increased protection against the development of cancer. The CD8+ cytotoxic cell subset is vital in killing a large variety of viral-infected and tumor cells. IL-2 augments the activities of both these cell types. IL-2 may also have an important, but as yet uncertain role in the development of T cells in the thymus.[2] Clinical trials have been conducted on the use of IL-2 for the treatment of cancer. The results of the early trials indicated that IL-2 therapy was useful in diminishing certain types of tumors, but there were serious side effects such as capillary leak syndrome, hypotension, fever, and rash7 . However, treatment regimens that used low doses of IL-2 or intermittent rather than constant administration of IL-2 caused fewer side effects while maintaining efficacy. Another important breakthrough in IL-2 therapy has been the construction of a hybrid IL-2/polyethylene glycol (PEG) molecule that has a longer half-life in the body, facilitating that administration of lower doses.[8]

One potential drawback of IL-2 therapy, however, is that it can stimulate the activation of HIV-infected cells, and this results in the production of more virus.[9] Therefore it is imperative to co-administer an anti-viral agent with IL-2 to offset this effect.[10]

In one recent study, HIV-positive individuals were administered PEG/IL-2 and AZT.[8] After 4 months their CD4 cells had increased slightly, as did the ability of their CD8+ cytotoxic cells to recognize viral-infected cells. Their NK cells also had elevated levels of cytolytic (killing of viral-infected cells) activity. Apparently the IL-2 did not accelerate HIV production since there were no increases in proviral DNA in CD4+ T cells, and no increases in p24 antigen levels. Similar results also were obtained in an earlier study.[11] Therefore, it is possible that IL-2 therapy might be useful as co-treatment to slow the progression of HIV, or as treatment for a variety of HIV related opportunistic infections such as CMV, Herpes Simplex, Kaposi's sarcoma, or lymphoma. These possibilities are currently being tested. Three trials are in progress testing the use of IL-2 in combination with antivirals, or in combination with antivirals and thymosin (a thymic hormone) for the treatment of HIV. Clinical trials for the treatment of AIDS-related diseases include IL-2 in combination with ganciclovir for the treatment of CMV retinitis, IL-2 in combination with retrovirals for the treatment of Kaposi's sarcoma, and ultra low dose IL-2 for the treatment of non-Hodgkin's lymphoma.[12] The results of these trials will be important in determining the potential uses of IL-2.

References

1. Kovacs JA, Baseler M, Dewar RJ, et al.. Increases In CD4 Lymphocytes With Intermittent Courses of Interleukin-2 In Patients With Human Immunodeficiency Virus Infection. N Engl J Med 1995;332: 567-75.

2. Smith KA. 1988. Interleukin-2: Inception, Impact, and Implications. Science 240: 1169-1176.

3. Chehimi J, Valiante NM, D'Andrea A et al. 1993. Enhancing effect of natural killer cell stimulatory factor (NKSF/interleukin-12) on cell-mediated cytotoxicity against tumor-derived and virus-infected cells. Eur. J. Immunol. 23: 1826-1830.

4. Clerici M and Shearer GM. 1993. A Th1 _> Th2 switch is a critical step in the etiology of HIV infection. Immunology Today 14: 190-191.

5. Fan J, Bass HZ, and Fahey JL. 1993. Elevated IFN-gamma and decreased IL-2 gene expression are associated with HIV infection. J. Immunol. 151: 5031-5040.

6. Miedema F. 1992. Immunological abnormalities in the natural history of HIV infection: mechanisms and clinical relevance. Immunodefic. Rev. 3: 173-193.

7. Sosman JA, Hank JA, and Sondel PM. 1990. In vivo activation of lymphokine-activated killer activity with interleukin-2: prospects for combination therapies. Semin. Oncol. 17(1): 22-30.

8. Wood R, Montoya JG, Kundu SK et al. 1993. Safety and efficacy of polyethylene glycol-modified interleukin-2 and zidovudine in human immunodeficiency virus type 1 infection: A phase I/II study. J. Infect. Dis. 167: 519-525.

9. Poli G and Fauci AS. 1992. The effect of cytokines and pharmacological agents on chronic HIV infection. AIDS Res. Hum. Retroviruses 8: 191-197.

10. Fauci AS. 1993. Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science 262: 1011-1018.

11. Clark AG, Holodniy M, Schwartz DH et al. 1992. Decrease in HIV provirus in peripheral blood mononuclear cells during zidovudine and human rIL-2 administration. J. Acquir. Immuno Defic. Syndr. 5:52-59.

12. American Foundation for AIDS Research (AMFAR), AIDS/HIV Treatment Directory, Vol. 6, Number 4, July 1993.

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