Interleukin-2 Immunotherapy and AIDS-Related Cytomegalovirus Retinitis

Abstract

Cytokines are small proteins produced by T lymphocytes that mediate immune responses. Those produced by the CD4+ Th1 subset induce cell-mediated immunity, whereas those produced by the CD4+ Th2 subset are more efficient at stimulating immunoglobulin production. The goal of cytokine immunotherapy is prevention or reduction of disease progression through stimulation of cell-mediated immunity (i.e., immune reconstitution) by administration of an exogenous Th1 cytokine such as interleukin-2 (IL-2). Cytokine immunotherapy has its origins in cancer immunobiology where IL-2 has been used successfully to manage several human cancers (metastatic melanoma, acute myelogenous leukemia, and metastatic renal cell carcinoma). More recent work has demonstrated cytokine immunotherapy to be effective at improving immune responses in patients with HIV-1 disease. To explore cytokine immunotherapy for sight-threatening AIDS-related human cytomegalovirus (HCMV) retinitis, we developed a mouse model of experimental murine cytomegalovirus (MCMV) retinitis that employs mice with MAIDS, a retrovirus-induced immunodeficiency syndrome. Systemic cytokine immunotherapy with IL-2, but not with interleukin-12 (IL-12), provides absolute protection against MAIDS-related MCMV retinitis by stimulation of the perforin-mediated pathway of cytotoxicity used by natural killer cells and cytotoxic CD8+ T cells to kill virus-infected cells. Our findings warrant additional studies on the use of cytokine immunotherapy for management of HCMV retinitis (and possibly other opportunistic infections) during HIV-1-induced immunodeficiency. We envision systemic cytokine immunotherapy as an altemative or adjunct to traditional antiviral chemotherapy for optimal management of AIDS-related HCMV retinitis.

The Role of CD4 T Cells in the Pathogenesis of Murine AIDS

“…It has generally been accepted that a Th1/Th2 imbalance underlies various immune diseases. In HIV-infected patients and LP-BM5-infected mice, T-cell proliferation and Th1 cytokine (IL-2 and IFN-␥) production have been reported to decline, while Th2 cytokine (IL-4, IL-5, IL-6, and IL-10) and immunoglobulin production increase (4,5,10,12,26,34,45,49,57).…”

“…There is some evidence suggesting that a Th2-type cytokine response is often associated with progression to AIDS in HIV-positive individuals (4,5,10,12,34,49,57). Thus, it seemed important to study here the question of whether the Th1 and Th2 subsets were differentially able to mediate LP-BM5-induced MAIDS pathogenesis.…”

Continued Decline of Aqueous Interleukin-8 After Multiple Intravitreal Injections of Ganciclovir for Cytomegalovirus Retinitis

“…7 Multiple intravitreal injections of ganciclovir or foscarnet appeared to be well tolerated and improvement of the retinitis was observed, either in AIDS patients 8,9 or in non-AIDS patients. 4,10 Previous studies implied that inflammation cytokines, including interleukin (IL)-2, [11][12][13][14] IL-4, 15 and IL-17, 16 may be involved in the development of CMVR by influencing the patient's susceptibility to it. However, to our knowledge, these previous studies about the relationship between inflammation cytokines and CMVR are generally based on animal or cell studies.…”

Suppressor of Cytokine Signaling 1 (SOCS1) and SOCS3 Are Stimulated within the Eye during Experimental Murine Cytomegalovirus Retinitis in Mice with Retrovirus-Induced Immunosuppression

“…We have used the MAIDS model of MCMV retinitis as an experimental model for AIDS-related HCMV retinitis to investigate humoral immunity (27), cellular immunity (28,29), cell death pathways (26), and a number of individual cytokines for their relative roles during retinal disease onset and development. Among the cytokines we have examined to date are tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), interleukin-2 (IL-2), IL-12, IL-4, IL-10, and IL-17 (22,23,(30)(31)(32)(33). The discovery by other investigators (34)(35)(36)(37) of the suppressor of cytokine signaling (SOCS) family of host proteins, which negatively regulates signaling induced by antiviral IFNs and other cytokines, such as IL-6, prompted us to reassess our concepts of how cytokines mechanistically impact the pathogenesis of AIDS-related HCMV retinitis.…”