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Potentiation of the immune system by cationic amphiphilic drugs
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trafficking in response to an enkephalin analogue called DAMGO, and morphine. They found that low concentrations of DAMGO were able to cause the endocytosis of morphine-liganded MOR, a phenomenon they ascribe to receptor oligomerization. DAMGO also reduced the morphine-induced
TRENDS in Pharmacological Sciences Vol.23 No.4 April 2002
superactivation of the cAMP pathway and reduced morphine tolerance in an animal model of nociception. The results indicate that MOR agonists with a strong capacity to induce receptor endocytosis might provide safer pain relief than the traditional opiates. [He, L. et al. (2002) Cell 108, 271–282] AB
161
This month’s In Brief articles were written by David Cutler ([email protected]) and Ann Barbier ([email protected])
Letters
Potentiation of the immune system by cationic amphiphilic drugs Selective enhancement of cell-mediated responses is likely to be therapeutically favourable against intracellular pathogens such as viruses. In this context, dendritic cells (DCs) play a pivotal role in the presentation of antigens to lymphocytes and the regulation of the T-cell proliferative response. CD4+ T-cell dysfunction and increased apoptosis of activated lymphocytes are prominent features of infection with HIV-1. Indeed, several studies have demonstrated the important role of HIV-specific CD4+ helper and CD8+ cytotoxic T-cell responses in the control of HIV-1 infection. However, the inability to generate an efficient natural antiviral activity in AIDS patients could be associated with a failure of antigen presentation by DCs [1,2]. Despite increasing knowledge of the regulation of the immune response at the molecular level, few rationally based immunoregulatory drugs are available. Cationic amphiphilic molecules are characterized by a structure exhibiting a bulky hydrophobic core and a nitrogenlinked positive cation. These amphiphilic compounds interact strongly with membranes and are able to interact with numerous other cellular targets [3]. We have identified such a compound, AY9944, that can restore the immune response by enhancing CD4+ T-cell proliferation in lymphocytes from AIDS patients and selectively favouring the expression of immunoregulatory cytokines [3,4]. More recently, we described the immunomodulatory effect of another amphiphilic cationic molecule: a new phenothiazine derivative, aminoperazine [5]. This molecule can increase the http://tips.trends.com
antigen-specific DC-driven proliferation and differentiation of HIV-infected and non-infected normal donor cells in vitro in addition to T cells from HIV-infected patients, and can also increase anti-HIV cytotoxic T lymphocyte (CTL) activity [5]. The consequence of infection with HIV-1 is a marked loss of T-cell function. The recent use of highly active antiretroviral therapy (HAART) in HIVinfected patients has been shown to increase CD4+ T-cell counts and improve the proliferative response to recall antigens, but HIV-specific T-cell responses are rarely restored. Furthermore, a recent report indicates that treatment of acute HIV infection with HAART can lead to a reduced CD8+ T-cell immune response against AIDS virus [6]. The reduced efficacy of current antiretroviral regimens in reconstituting the immune system suggests that immune-based therapy combined with HAART remains an important objective of AIDS research. Such combination of immunization with HAART might thus result both in the induction of immune responses and in viral load reduction with the caveat of antigen presenting cell (APC) dysfunction in AIDS. Agents that enhance DC-driven proliferation might therefore help induce HIV-1-specific responses in infected patients receiving HAART. Our findings could have implications for both basic research and clinical practice. From the laboratory perspective, it would be desirable to study and describe novel cationic amphiphilic molecules with the aim of characterizing their mechanisms of action. Regarding clinical application, the combination of these molecules with HAART might represent a pharmacological means for HIV-1 eradication. The incorporation of these molecules in the design of current antiviral vaccines that alone provide poor immune response might be an important strategy.
In conclusion, we suggest that cationic amphiphilic molecules might be used for restoring the immunity of immunocompromised patients. This study has potentially important implications for the use of these molecules as an effective immunotherapy. Furthermore, these agents might also be exploited as vaccine adjuvants [7]. Ammar Achour Université René Descartes Paris V, Laboratoire des Interférons et de la Sarcolectine, Centre Biomédical des Saint Pères, 45 Rue des Saint Pères, 75270 Paris Cedex 06, France. e-mail: [email protected] References 1 Knight, S.C. (1996) Bone-marrow-derived dendritic cells and the pathogenesis of AIDS. AIDS 10, 807–817 2 Fan, Z. et al. (1997) Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection. J. Immunol. 159, 4973–4982 3 Achour, A. et al. (1998) Restoration of the immune response by a cationic amphiphilic drug (AY 9944) in vitro: a new approach towards chemotherapy against HIV-1. Antimicrob. Agents Chemother. 42, 2482–2491 4 Achour, A. (2000) Increased β chemokines production in peripheral blood mononuclear cells derived from HIV-1-infected individuals by a cationic amphiphilic drug (AY 9944) in vitro. AIDS 14, 1454–1455 5 Lu, W. et al. (2001) Enhanced dendritic cell-driven proliferation and anti-HIV activity of CD8+ T cells by a new phenothiazine derivative, aminoperazine. J. Immunol. 167, 2929–2935 6 Stanford, S.A. et al. (2001) Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection. Proc. Natl. Acad. Sci. U. S. A. 989, 597–602 7 Achour, A. (2001) The cationic amphiphilic molecules as potential immunostimulants for HIV-1 infection. Int. J. Antimicrob. Agents 18, 275–276
Chemical name AY9944: trans-1,4-bis(chlorobenzylaminomethyl)cyclohexane)-dihydrochloride
0165-6147/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
trafficking in response to an enkephalin analogue called DAMGO, and morphine. They found that low concentrations of DAMGO were able to cause the endocytosis of morphine-liganded MOR, a phenomenon they ascribe to receptor oligomerization. DAMGO also reduced the morphine-induced
TRENDS in Pharmacological Sciences Vol.23 No.4 April 2002
superactivation of the cAMP pathway and reduced morphine tolerance in an animal model of nociception. The results indicate that MOR agonists with a strong capacity to induce receptor endocytosis might provide safer pain relief than the traditional opiates. [He, L. et al. (2002) Cell 108, 271–282] AB
161
This month’s In Brief articles were written by David Cutler ([email protected]) and Ann Barbier ([email protected])
Letters
Potentiation of the immune system by cationic amphiphilic drugs Selective enhancement of cell-mediated responses is likely to be therapeutically favourable against intracellular pathogens such as viruses. In this context, dendritic cells (DCs) play a pivotal role in the presentation of antigens to lymphocytes and the regulation of the T-cell proliferative response. CD4+ T-cell dysfunction and increased apoptosis of activated lymphocytes are prominent features of infection with HIV-1. Indeed, several studies have demonstrated the important role of HIV-specific CD4+ helper and CD8+ cytotoxic T-cell responses in the control of HIV-1 infection. However, the inability to generate an efficient natural antiviral activity in AIDS patients could be associated with a failure of antigen presentation by DCs [1,2]. Despite increasing knowledge of the regulation of the immune response at the molecular level, few rationally based immunoregulatory drugs are available. Cationic amphiphilic molecules are characterized by a structure exhibiting a bulky hydrophobic core and a nitrogenlinked positive cation. These amphiphilic compounds interact strongly with membranes and are able to interact with numerous other cellular targets [3]. We have identified such a compound, AY9944, that can restore the immune response by enhancing CD4+ T-cell proliferation in lymphocytes from AIDS patients and selectively favouring the expression of immunoregulatory cytokines [3,4]. More recently, we described the immunomodulatory effect of another amphiphilic cationic molecule: a new phenothiazine derivative, aminoperazine [5]. This molecule can increase the http://tips.trends.com
antigen-specific DC-driven proliferation and differentiation of HIV-infected and non-infected normal donor cells in vitro in addition to T cells from HIV-infected patients, and can also increase anti-HIV cytotoxic T lymphocyte (CTL) activity [5]. The consequence of infection with HIV-1 is a marked loss of T-cell function. The recent use of highly active antiretroviral therapy (HAART) in HIVinfected patients has been shown to increase CD4+ T-cell counts and improve the proliferative response to recall antigens, but HIV-specific T-cell responses are rarely restored. Furthermore, a recent report indicates that treatment of acute HIV infection with HAART can lead to a reduced CD8+ T-cell immune response against AIDS virus [6]. The reduced efficacy of current antiretroviral regimens in reconstituting the immune system suggests that immune-based therapy combined with HAART remains an important objective of AIDS research. Such combination of immunization with HAART might thus result both in the induction of immune responses and in viral load reduction with the caveat of antigen presenting cell (APC) dysfunction in AIDS. Agents that enhance DC-driven proliferation might therefore help induce HIV-1-specific responses in infected patients receiving HAART. Our findings could have implications for both basic research and clinical practice. From the laboratory perspective, it would be desirable to study and describe novel cationic amphiphilic molecules with the aim of characterizing their mechanisms of action. Regarding clinical application, the combination of these molecules with HAART might represent a pharmacological means for HIV-1 eradication. The incorporation of these molecules in the design of current antiviral vaccines that alone provide poor immune response might be an important strategy.
In conclusion, we suggest that cationic amphiphilic molecules might be used for restoring the immunity of immunocompromised patients. This study has potentially important implications for the use of these molecules as an effective immunotherapy. Furthermore, these agents might also be exploited as vaccine adjuvants [7]. Ammar Achour Université René Descartes Paris V, Laboratoire des Interférons et de la Sarcolectine, Centre Biomédical des Saint Pères, 45 Rue des Saint Pères, 75270 Paris Cedex 06, France. e-mail: [email protected] References 1 Knight, S.C. (1996) Bone-marrow-derived dendritic cells and the pathogenesis of AIDS. AIDS 10, 807–817 2 Fan, Z. et al. (1997) Cultured blood dendritic cells retain HIV-1 antigen-presenting capacity for memory CTL during progressive HIV-1 infection. J. Immunol. 159, 4973–4982 3 Achour, A. et al. (1998) Restoration of the immune response by a cationic amphiphilic drug (AY 9944) in vitro: a new approach towards chemotherapy against HIV-1. Antimicrob. Agents Chemother. 42, 2482–2491 4 Achour, A. (2000) Increased β chemokines production in peripheral blood mononuclear cells derived from HIV-1-infected individuals by a cationic amphiphilic drug (AY 9944) in vitro. AIDS 14, 1454–1455 5 Lu, W. et al. (2001) Enhanced dendritic cell-driven proliferation and anti-HIV activity of CD8+ T cells by a new phenothiazine derivative, aminoperazine. J. Immunol. 167, 2929–2935 6 Stanford, S.A. et al. (2001) Reduction in CD8+ cell noncytotoxic anti-HIV activity in individuals receiving highly active antiretroviral therapy during primary infection. Proc. Natl. Acad. Sci. U. S. A. 989, 597–602 7 Achour, A. (2001) The cationic amphiphilic molecules as potential immunostimulants for HIV-1 infection. Int. J. Antimicrob. Agents 18, 275–276
Chemical name AY9944: trans-1,4-bis(chlorobenzylaminomethyl)cyclohexane)-dihydrochloride
0165-6147/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.