- Email: [email protected]
Immunotherapy of human immunodeficiency virus infection
TiPS - March 1991IVo!. 121 olizing Enzymes: Cenetia.
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Toxicology (Ingkman-Sundberg, M., Custafsson. J. A. and @genius, S., ads), Karolinska Institute, Stockholm Yue, Q. Y. et al. (199) Lancef ii, 870 Mortimer, 0. et al. (1990) Clin Phammcool. Ther. 47, 27-35 Yue. Q. Y., Svensson, J-O., Alm, C., Spqvist, F. and Sawe, J. (1989) Br. 1. C/in. Ph4t7~4col. Z&629-637 Yue, Q. Y., Svenuon, J-O., Aim, C., Sjvist. F. and Sawe, J. (1989) Br. /. C/in. Phmacol. 28,639-645 Woolhouse, N. M., Eichelbaum, M.,
26 27 28 29
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Oates, N. S., Idie. 1. R. dnd Smith, ?. L. (1985) Clin. Pharmocol.Ther. 37,512-521 Tyndale. R. F., Inaba, T. and Katow, W. (1989) Dncg Metab. Dispos.17, 334-340 Whittaker, M. (1986) Ckrr!inesterase, Karger Choneim, M. M. et 41. (1981) Clrrl. Phnmmcol.Ther. 29,74%756 Kumana, C. R., Lauder, I. J., Chan, M., Ko, W. and Lin, H. J. (1987) Eur. /. Clir. Pharmncot.32,211-215 Rosenblat, R. and Tang, S. W. (1987) Cna. J. Psychinlr.32,270-274 Bertilrwn, L. rt al. (1989) Clb~.Pbamln-
Immunotherapy of human immunodeficiency virus infection John W. Hadden HIV infection results in the destruction of the thymus-dependent cellular immune syskm and death due to opporfunisrir infection and malignancy. fmmunosuppressitle influences (other sexually or Wood-transmitted Cruses, HIV-dcriued peptides, semen, poor nutrition, drugs, efc.) favor the progression of the disease. Although immunorestorative agsrfi may be expected to delay progression of the disease, John Hadden argues that no agent has yet proven usefur in reuersing the immunodcficiency in full-blown AIDS. However, two thymomimetic drugs, isoprinosine and diethyldithiocarbama!e, inhibit fhe development of infections in patients with pre-AIDS in large multicenter trials, and preliminary data from trials with two thymomimefic peptides, thymopentin and ImReg-1, in pre-AIDS patients are encouraging.
HIV infection and AIDS are complicated and expensive in terms of human suffering, amount of care and financial cost. Like the treatment of cancer, palliation is necessary but difficult. Between prevention and cl;re lies a complex area of management that has spawned three important therapeutic efforts: vaccine development as a strategy of management as well as prevention; antiviral therapy to p-vent the p*agression of infection; and immunorestorative therapy as a strategy to reduce the rate of progression of the disease and to prevent opportunistic infections. Vaccine development for both prophylactic and therapeutic purposes is receiving major attention, /.
W. Hadden L Director of lhr iIiltMW-
pJtrmwolc?qy Dhiow. Utduersity 01 Sottth
Florida Mediral Cortege.Tatrrpr, FL 33612. USA.
and will not be reviewed here’“. The virus has been fully described and the surface glycoprotein gp16O/gpl20 has been detailed with respect to its conserved sequences. Knowledge of viral surface epitopes necessary for binding to the CD4 receptor of helper T lymphocytes and those expressed on HIV-infected cells should provide the basis for potent synthetic vaccine formation using synthetic adjuvants such as the muramyl peptides and synthetic, detoxified lipid A. Antiviral therapy has developed in a remarkable way. Zidovudine (AZT, azidothymidine) is now licensed and widely used in the palliation of the condition of AIDS initial testing with patients; lower, less toxic doses indicates that it may be useful prophylactically in not=vmptomatic HIVpositive patients’. Many other antiviral drugs are under develop
col.Thrr.45, 348-355 32 Lin, K. M. et al. (1988) Psvrhouhenncology%,365-369
~
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33 Schaefer, 0. (1986) in EIhrtir Drffermres in Rearfio!ts 10 Drugs nnd Xenobiolirs (Kalow. W., Goedde, H. W. and Agarwal. D. P., eds). PP. 77-83, Liss 34 Bmsen, K. and Cram, L. F. (1989) EIW. /. Clin. Phnnnacol.36,537~547 35 Suddendorf, R. F. (1%9) Pubf. Health Rep. 104.615-620 36 Kassam,J. P ,Tang. B. K.. Kadar. D. and Kalow. W. (1989) Drag Melab. Dispos. 17,567-572
ment (e.g. 2’,3’-dideoxyinosine and 2’,3’-dideoxycytidine or under study (2’,3’-dideoxythymidine, etc.; see Ref. 5). The notion that companion viruses (e.g. EBV, CMV, herpes virus-6, HTLV-1) are critical in the acceleration of the development of AIDS in genera! and Kaposi’s sarcoma in particular has spawned a number of antiviral approaches in which zidovudine treatment is combined with acyclovir, ribaviran or AS-101’. Although these approaches offer hope that longterm nontoxic antiviral therapy may be possible, zidovudineresistant viruses are increasingly being detected. More sensitive detection techniques indicate that the number of T cells infected in HIV-positive patients is higher than previously thought (i.e. 0.1~1.0% versus 0.01% of T lymphocytes’). This emphasizes the fact that a single transcript of the virus dooms the infected T cell even though other induction events are required to yield viral replication. Since transcription has already taken place, the ultimate fate of the virus is not affected by a reverse transcriptase inhibitor like zidovudine; other antiviral therapies, even those acting at subsequent steps of viral replication, will therefore prove ineffective in eradicating the virus. The only means known to eradicate a virus is through the immune response, and this is the focus of this review: immunorestorative therapy in HIV disease. Although their relatij-e importance and detailed mechanisms are not known, neutralizing antibody, antibody-dependent ceflular cytotoxicity, cytotoxic T cells and natural killing mechanisms are thought to be the four key factors in defense against HIV and
TiPS - March 1991 [Vol. 121
AIDS: markem and drugs The human immunodeficiency virus (HIV)is the cause of the AIDS epidemic. This blued-borne virus is transmitted through contact with blood or semen of infected individuals. On entry to the body, it binos to the CD4 molecule on the surfaceof the major subset of thymus-derived lymphocytes cakd T belpcr lyrnphocytes. It enters and becomes latent within the T lymphocytes.immunity to the virus develops involving antibody and cytotoxic CM+ lymphocytes. Antibody-
coated viruses may enter other c4s like macmphages and glial cells, by binding to their surface immunoglobulin receptors(F&s). Thus despite the presence of the immune response, the virus replicatesto infect other CD4+ and Fc+ cells. Following a long latent period, on average ten years, the progressive loss of CD4+ T lymphocytes results in an inversion of the normal 2: 1
its companion viruses as well as the other opportunistic pathogens that invade as a result of the immunodeficiency. The immunotherapy of AIDS Immunotherapy in AIDS at the end stage of HIV infection was
predicted to be an unsuccessful strategy*, and a number of subsequent reviews of the collected studies’*“’ document the fulfilment of this prediction. Immunotherapy in the absence of con-
current antiviral therapy in AIDS has not been effective in reversing the immunodeficiency. Two preparations of interferon-n (IFN-a; Schering and Hoffman-LaRoche) have been licensed by the Food and Drug Administration (FDA) for treatment of Kaposi’s sarcoma. IFN-a is effective alone (20-40% major response rates) and in conjunction with zidovudine (>60% response rate”), but it does not reverse immunodeficiency. Also, uniike the anticancer chemotherapy generally employed in AlDS-independent Kaposi’s sarcoma, it is not immunosuppressive and has not been proven to reduce the incidence of infections. Various types of transplantation techniques have been attempted: ?? Bone marrow transplantation is a widely used treatment for severe combined immunodeficiency (SCID) and certain forms of leukemia. While it is expensive and is associated with high morbidity, in these diseases it can be curative. By contrast, its use in AIDS has been generally unsuc-
cessful .
A recent reporP
using bone marrow transplantation plus zido??
ratio of helper (CM+) to supprewor/cytotoxic (CDe’) lymphocytes. This is associated with dtnical hnmunodeficiency, with the developmart of suswptibillty to infections and malignancies such aa Rapooi’s nreoma. During the final phase of the fllneaa (AIDB),the virus andviralantigenslikepllappearintherkubt&md Sgum mar+ of fympboid inktion like &mrao&Wm and neqfuin increase, indiathtg a poor
Prognosis Antiviral agents like zidovud@ (azidothymidlne; AZT) inhibit vfraf repfication but do not em&ate it. Zidovudine effectively slows the pmgma&m of the
final phases cf AIDS and also slows the pmgmasion from pm-AIDS to full-blown AIDS. Toxicity and cost limit its use. &ny ahematives and complementary forms of therapy are under study.
vudine claims success in eradicating virus, but conclusions are premature since the patient died and long-term follow up was impossible. ?? Transplantation of thymic tissue and adoptive transfer of heterologous lymphocytes has been unsuccessful in AIDS”. a Ex vivo expansion of autologous lymphocytes with interleukin 2 (IL-2) and zidovudine is under study and theoretically may offer some palliation, if economically feasible. e Adeptive transfer of virus-inactivated serum from individuals with high titer neutraiizing antibody against HIV is another approach being tested6; preliminary results indicated reduced p24 antigenemia, increased CD4+ T lymphocytes, and apparent improvement in the clinical status of a number of the patients. Intravenous immunoglobulin therapy is generally considered to be useful and nontoxic in the treatment of pediatric AIDS patients for the management of bacterial infections. A multicenter phase !I! tria! with zidovudinc in 250 patients is underway to confirm this widely accepted but unproven notion’. A number of anecdotal reports indicate that such therapy may improve the course of AIDS and Art?+related complex (ARC) in adult patients and a multicenter trial has been initiated to test this using intravenous immunoglobulin therapy alone and in combination with zidovudinet3.
Ir.iti;i! studies with recombinant IL-2 in AIDS were negative’+“; however, with persistent i-v. in-
fusion of high doses, lymphocytosis without enhanced viral recovery was observed. Toxicity is associated with a ‘flu-like’ syndrome, fluid accumulation, and increased bacterial infectiorts. A number of combined IL-2 and zidovudine phase I protocols are in progress. Schwartz et al.” treated several AIDS patients with this combination: preliminary data indicated that the combination is compatible, that the toxicity levels are acceptable and that the ability of IL-2 to inorraK CD4+ T-cell counts and cehlat cytotoxicity, and to enhance &in test reactivity was not parented by zidovudine. No increase in vial antigenemia or viral recovery was observed. The authors condude that further study is warranted. A number of trials of combined immunotherapy and antiviral therapy are in progress in AIDS patients. However, the ensuing discussion should make it clear why relatively little can be expected. Immunorestoration &I ARC and
asymptontaticHIVi&ction IFN-ar modulates various immune responses. Thus it enhances killer .cell activity by lymphocytes, mac@tages and naiural killer ceBa while depressing lymphocyte proliferation and S;?cretO responses. Two recent reports’7 Jb indicate that IFN-IX treatment of pre-AIDS patients reduces HIV virus recovery, p24 antigenemia, and opportunistic infection despite toxic side-&e&s. Several combined protocoIs (IFNr?*vith diethyldithiocarbamak, see below, IL-2 or ridsvudine) are underway.
‘JWS- Marc!r 1991 IVoL 12! Am&en is a polynucleotide derivative of poly(IC) with spaced uridines to provide RNase cleavage sites. It has anti-HIV activity in vitro. It also induces interferon and acts as an immunomodulator in oivo, which is characteristic of other interferon inducers including natural killer cell activation. However, despite this activity and despite the lack of toxic sideeffects observed with poIy(lC), a multicenter, double-blind phase II study was terminated early due to lack of activityb. ImReg-1 (see Fig. 1) is a dialysed leukocyte extract from normal donors in which the oligopeptides Tyr-Gly-Cly and Tyr-Gly are thought to be the nonspecific active components. ImReg-1 modulates lymphokine production in vitro and enhances dermai skin test responses in uivo when given intracutaneously with tetanus toxoid antigen. In a multicenter trial” totaRing 141 ARC patients, 93 were treated with SmReg-1 bi-weekly and showed a significantly reduced tendency to progress to a clinically relevant endpoint (4.3% versus 25%) or to AIDS (3% versus 17%). Marginally significant changes in CD4+ counts and symptom scores were also observed. No toxicity was observed. A larger confirmatory trial is planned. Methyldithiocarbamate (OTC) jlmuthiol) is an orally active thymomimetic drug that is more active and less toxic than its predecessor levamisole’s, Multicenter controLled studies1950 in 143 symptomatic pm-AIDS patients indicate that OTC decreases symptoms and AIDS conversion (13% to 4.5%) and tends to increase CD4* lymphocytes. Kaplan et aLa reported that decreased lymphadenopathy occurred in most patients with CD4 counts greater than ZOO,in a small randomized controlled trial. These findings have been extended in a large multicenter study of AIDS and ARC patients heated orally with 400mgm-2 OTC weekly, where 389 patients showed a significant (-50%) reduction in opportunistic infections in both AIDS and ARC subjects=. Although the number of T cells expressing CD4 increased in he MT-treated group (255 to 30 mm-‘), they did not decline, as had been exwcted, in the control
group (unchange\; at 270 mm-‘); the changes were, therefore, not significant. No significant toxicity was observed. A 1600-patient trial is in progress in Europe to determine the effect of DTC on asymp tomatic HIV-positive patients. Isoprinosine, an inosine-containing complex, is a thymomimetic drug that induces T-cell differentiation and promotes Tcell function in oitrs and in aivo’s. lnitial controlled trial!?’ demonstrated significant increases in CD4 counts and natural killer cell activity and significant decreases in symptoms. Fewer cases of ARC converted to AIDS in patients with progressive generalized lymphadenonathv and mean CD4 counts greate; th& 500 mme3. Several multicenter doubleblind triafs have been completed. In the USA a trial of 696 HIVpositive symptomatic patients with CD4 counts less than 400 mmv3 did not reveal significant immunological or clinical results (see Ref. 6). By contrast, a Scandinavian trials with 8(56Hlv-positive symptomatic ARC patients with mean CD4 counts greater than 425 showed a significant reduction in ARC to AlDS conversion (4% to 0.5%) over a six month period, although no significant immune correlates were obtained. tn Italy, from a trial with 553 asymptomatic HIV-positive iqlividualsx+, isoprmosine treatment -wdb8ssociakd with no new infections; 12 controls developed infections. In this study, decreawd symptoms, preservation
of 08 ratios and an increase in natural killer cells were observed in the treated group. No toxicity was observed. These studies indicate that isoprinosine treatment benefits HIV-positive patients by preventing the development of infection only when CD4’ lymphocyte counts are greater than 400 mm-‘. Thyrnopentir. is the pentapeptide active site of thymopoietin, a chemically defined thymusderived peptide having thymomimetic activitv irr vitro and in viuo. Initial co&roRed studiessr2B with thymopentin showed positive effects. On the basis of these findings, a blind multicenter tintrial- involving 47 thymo treated asymptomatic H Jen-positive and ARC patients and 44 placebo-treated controls was set up. Preliminary results indicated that four controLs m to constitutional symptoms or AIDS, while none of the treated patients progressed (p
TiPS - March 1991 Wol.
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Years fig. 2 Therapymodelh7rHIV intec/iim. current status of immunorestontive therapy The most useful therapeutic approaches oriented toward improving the function of T lymphocytes in HIV disease involve two drugs, DTC and isoprinosine, and two peptides, thymopentin and ImReg-1 (Fig. 1) for use alone or in combination with antiviral therapy. No significant side-effects with these agents have been noted; thus they are safe and no incidence of HIV activation has been uncovered. Their combined use with antiviral agents relies on the assumption that the antiviral agent8’ do not inhibit their activity. This remains to be determined. The total number of reported patients treated with these agents exceeds 2500, which underscores the statistical significance of the findings. The case for lmmunotherapy is no longer in doubt. The question remains as to how to perfect it. Figure 2 offers a schematic view of the current use of immunotherapy, which in this context would be nore appropriately termed ‘post-infection immunoprophylaxis’. The length of the latency period is variable, presumably related to other concomitant immunosuppressive influences. Zidovudine treatment should be reserved for AIDS itself. Its eartier use may or may not ultimately be fruitful in terms of prolongation of life, because of the risk of Development of HIV resist-
ance. Combined use of zidovudine or other antivirals with immunotherapy based upon the experience with isoprinosine, DTC, ImReg-1 and thjiinopentin appears to be beneficial when CD4 counts are greater than 4OGmmm3. A more detailed analysis of lymphocyte dysfunction in early HIV infection is warranted to determine the effects of soluble serum-borne inhibitors on Tlymphocyte function. Conceptually, it will be relevant to introduce immunotherapy at a point before the deve!opment of poor prognostic indicators in asymptomatic HIV-positive individuals, e.g. p41 antigenemia or elevated neopterin or a-microglobulin levels. In early HIV infection, before the onset of AIDS, the initial incidence of infected CD4 lymphocytes was previously thought to be extremely low (1: 1OooO)and even with recent estimates of the frequency of HIV transcript-bearing CD4+ cells (0.1-l%) the degree of immunosuppression in early infection is out of proportior. to the frequency of cells affected. When CD4 lymphocyte counts are corrected for in vitro tests of lymphoproliferative responses, the degree of functional impairment is also out of proportion to the loss of CD4+ cells. Thus, a large number of lymphocytes are dysfunctional. This ‘pan anergy’ i.e. a general defect in cellular immune function - presumably
121
retrovirus-induced
or -protiuced immunosuppressive factors and/or autoantibodies to T cells. Clarification of these factors and their mechanisms is needed. The molecular strategies to augment T-cell function with thymomimetic agents in pre-AIDS appear to depend on the presence of lymphocytes whose function, when restored, will benefit the host and not result in the activation and spread of virus. Ideally the system should be replenished with virus-free T lymphocytes produced by the thymus. The thymus involutes and eases fc function relatively early in life and thymic secretory capacity for thymic hormones declines in midlife at a time corresponding to female gonadal menopause. Thus, many conclude that the thymus is nonfunctional. However, studies of radiation injury, cancer chemotherapy, and bone manow transplantation for leukemia indicate that the thymus can pmcess precursors to restore the T-&l system in the periphe$l. It appears that when the need arises, signals develop to induce thymic T-cell processing function. These signals have not been identified, but recent evidence implicates both interleukins and pituitary factors (see Ref. 10). The thymus is destroyed in AIDS with obliteration of both epithelial and lymphoid components. Once the thymue has been deshoyed, T cells cannot be generated anew. It is not clear at what stage of HIV infection the thymus loses its capacity to replenish. Obviously, the administration of thymotmphic substances to enhance T-cell replenishment should logically precede thymus destruction. A useful therapeutic s&&w would be to employ thyrnic and pituitary hormones, and interleukins, to stimulate T-ceJl development provided that a residual, marginally functioml thymus still exists. In the context of HIV infection, this therapy would include antiviral therapy. Cl
cl
Cl
Immunorestorative therapy per SC has not proven useful in fully developed AIDS. EN-u alone and in conjunction with zidovudine is usetul in the m Kaposi’s sarcoma inaYznzto;! Al tive immunotherapy with Lv. im-
TiPS - Mnrch 2991[Vol. 121 munoglobulin, high titer anti-HIV sera, and ex viuo IL-2-expanded T lymphocytes all remain realistic approaches alone and in conjunction with antiviral therapy, Marrow, thymus and lymphocyte transplants alone have not proven useful. The thymomimetic drugs isoprinosine and DTC significantly reduce disease progression and infections in large trials of H!V-positive pre-AIDS patients, particularly when CD4+ lymphocyte counts are greater than 400 mms3, and licensing seems warranted. Preliminary data with the thymominetic biologicals thymopentin and ImReg-1 suggest that their use in conjunction with antiviral therapy before the onset of AIDS may be helpful. Recent work on the important HI? surface epitopes for neutralizi?tg antibody and cytotoxic T cells makes possible new therapies with human monoclonal neutralizing antibody and synthetic vaccines to manage disease. Also, recent developments on the important intrathymic regulators (thymic hormones and interleukins) as well as extrathymic regulators (pituitary hormones and interkukins) make possible more complex strategies to improve T-ceil number and function. While cure at this point seems out of reach, combined therapies ative atints, and antiviral therapy offer the best prospects for enforcing viral latency and sustaining healthful, productive ezistence of those infected.
Referenles 1 Ada.*;. (lsw) Nofure 339,331-332 2 Bologesi, I?. P. (1989) S&arc 246, 123% 234 3 Girafd, M. (‘9%). Cancer Dclecf. Preu 14,411413 4 Volberding. F. A. et QL (1990) N. EqI. /. Med. 322,941-q 5 dcclcrq. ‘c. :199m 7.cnds PlturQlnco/. Sri. 11,1%205 6 Abmmr, D., Grieco, M., Cottiieb, M. and Bpeer, M., edr (1989) AIDS/H/V Erpnimrnfaf Tw&mwf. AMFAR Dirertory (Vol. 3, bio. 1) 7 Ho, D. D., Moudoil, T. and Alam, M. (1989) N. Et@. /. Mrd. 321,1621-1625 8 Hadden, J. W. (1984) in Ann. NY Acad. Sri. Vol. 437 (Belikoff, 1. J., T&stein, A. and Him&man, S. 2, ~45). y. 16-87, Hew York Academy of Sciences 9 Hadden, J. W. (1987) In AfDS Qrd Ofkcr MQ@rs&tiorts of HIV h&x-lion (Womuwr, C. P., Stahl, R. E. and Bottone, E. J., edr), pp. 992-1017. Nyes Publications
111 10 Hadden. J. W. (1989) in Aduances br lnrnruaopltlrrmacdogy 4 (Hadden, J. W. et d., ds), p. 19, Pegamon he55 11 Lane, H. C. (1989) AIDS 3 (Suppl. 1). 181s-185s 12 Holland, H. K. et Ql. (1989) Aafl. Inhrn. Mrd. 111.o~981 13 DeSimone, C. tr a! (1990) J. Clbr. Lab. Anal. 4.313-317 14 Schwartz, D. H., Skowron, G. and Merigan, T. c. Pmt. Sixth bt. con\. on AfDS, San FrQnciscoSB444 (abstr.) 15 Davey, V., Johnson, R. P. and Lane, H. C. (1989) Pm. Fifth hf. Con/. O” AIDS, Morrtreal W.B.Y 322 (absh.) 16 Brook, M. G. et al. (1989) Lance!i, 42 17 Gottlieb, A. A. et Qf. (1988) Proc. Folrrth Inf. COflf. O)I AIDS, Sfockholm 3048 (abstr.) 18 Hadden, J, W. (1985) in Syraposiumon Imm0Q0pkarmac0l0gy. Serc;;o Symposium (Miescher, P. A., Bolis, L and Chiooe, M., eds), pp. 183-192, Raven Press 19 Lang, J. M. rt al. (P-188)Lancr: ii, 702-706 20 LankJ. (1989) PIUC. Fifth M. Goof. O” AIDS, Moewtel W.B.P. 296 (abatr.) 21 Kaplan, C. S., Peterson, E. A., Yocum,
D. and Hesh. E. M. (1989) Lift St?.45, ...
I,,-IX 22Hersh, E. M.
ef 01.1. Am. Med. Assoc. (in
p55)
23 Clasky. A. I. and Gordon,]. (19%) Myth. Find. Exp. Clio. PhormQrol. 8, 3w 24 Bekwi, J. G.. Tsang, P. H., Wake. J. 1. and Roboz. I. P. (1987) /. Cfia. Lnb. Immmml. 24.155-161 25 Pedrrsen, C. tt al. (1990) N. Egl. /. Med. 322. X57-1763 26 DeSimrme, C. rt al. (1988) Mrd. Onr0l. Tumor Phormacothcr. 10.2~9-303 27 bcellini. W. et al. (1987) C/in. Exp. lmmunol.67.537-543 28 Silvestris, F., Gemone, A., Frassanito, M. and Dammacco,F. 11989)J. Lab. Clia Med. 113,139-w 29 Conant, M. A., Goldstein, G., Hirsch, R. L., Meyerson, L. A. and Kmmer, A. B. (1990) J. Cell. Biochem. (SuppI. 14D.148) UCLA Symposhrm on MoltcnlQr ond Cell Biology, San Francisco AIDS Meeting (abstr. L411) 3@ LUSttt. M. 1. C! Qr. (1989) TOo:iiO/. Aopl. PJIQ~QCOI. 101,32&339 31 Kelley, K. W. et al. (1986) Proc. Nat! Acad. Sri. USA 83,566~5667
.
The role of neuropeptideY In cardiovascularregulation Philippe Walker, Eric Grouzmann, Michel Burnier and Bernard Waeber Neumpeptidc Y (NPYJ is a 36 amino acid prptide present in the brain, the adrenal medulla and peripheral sympathetic nerves. The localization and mode of release of NPY led to the pmposal that this peptide plays an important mJe in modulating the contribution of the sympathetic nervous system to blood pressure control. In this paper Bernard Waeber and colleagues review the current knowledge about the mechanisms involved in NPYsignal transduction and the different mechunisms whereby NPY, released by the peripheral nervous system, may infJuence vascular tone and cardiac func!4n1.
Neuropeptide Y (NPY) was isolated for the first time in 191)2from porcine brain by Tatemoto’. It has since been the subject of numerous biochemical, physiological and pharmacological studies. This 36 amino acid peptide is a member of a family of structurally related peptides including peptide W (PYY) and the pancreatic polypeptide (PP). NPY is widespread in the central and peripheral nervous systems and is one of the most abundant neuropeptides found in the mammalian brain. Moreover, its amino acid sequence is remarkablyconserved P. WQfkrr nod E. Crownm~~r are Resrwch ASSOciQkS nod M. 6lwnier ead g. WfftbcrQrr r\ssistaat~ro@son in thr Diuisioaof Hypwfrnsior, Cwtrc HospWrr Uniwsffair~ VQQdois. 1011 L~rsnnrc, Swifxrlatld.
across species. NPY exerts a multitude of actions, both centrally and peripherallyr3. This review describes the peripheral actions of NPY that might participate in cardiovascular regulation. Localizatkm and release of NPY The development of anti-NPY antibodies has allowed the peptide to be localized using immunohistochemical techniques. NPY is present most abundantly in the perivascular nerve fibers of many organs, in pardcular around the cerebral, renal, coronary, mesonteric and femoral art&esU. In general, NPY-con:aining fibers are more abundant amund arteries than veins. Fibers around small arteries show mom immunoreactivity than nerve fibers around large
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Toxicology (Ingkman-Sundberg, M., Custafsson. J. A. and @genius, S., ads), Karolinska Institute, Stockholm Yue, Q. Y. et al. (199) Lancef ii, 870 Mortimer, 0. et al. (1990) Clin Phammcool. Ther. 47, 27-35 Yue. Q. Y., Svensson, J-O., Alm, C., Spqvist, F. and Sawe, J. (1989) Br. 1. C/in. Ph4t7~4col. Z&629-637 Yue, Q. Y., Svenuon, J-O., Aim, C., Sjvist. F. and Sawe, J. (1989) Br. /. C/in. Phmacol. 28,639-645 Woolhouse, N. M., Eichelbaum, M.,
26 27 28 29
30 31
Oates, N. S., Idie. 1. R. dnd Smith, ?. L. (1985) Clin. Pharmocol.Ther. 37,512-521 Tyndale. R. F., Inaba, T. and Katow, W. (1989) Dncg Metab. Dispos.17, 334-340 Whittaker, M. (1986) Ckrr!inesterase, Karger Choneim, M. M. et 41. (1981) Clrrl. Phnmmcol.Ther. 29,74%756 Kumana, C. R., Lauder, I. J., Chan, M., Ko, W. and Lin, H. J. (1987) Eur. /. Clir. Pharmncot.32,211-215 Rosenblat, R. and Tang, S. W. (1987) Cna. J. Psychinlr.32,270-274 Bertilrwn, L. rt al. (1989) Clb~.Pbamln-
Immunotherapy of human immunodeficiency virus infection John W. Hadden HIV infection results in the destruction of the thymus-dependent cellular immune syskm and death due to opporfunisrir infection and malignancy. fmmunosuppressitle influences (other sexually or Wood-transmitted Cruses, HIV-dcriued peptides, semen, poor nutrition, drugs, efc.) favor the progression of the disease. Although immunorestorative agsrfi may be expected to delay progression of the disease, John Hadden argues that no agent has yet proven usefur in reuersing the immunodcficiency in full-blown AIDS. However, two thymomimetic drugs, isoprinosine and diethyldithiocarbama!e, inhibit fhe development of infections in patients with pre-AIDS in large multicenter trials, and preliminary data from trials with two thymomimefic peptides, thymopentin and ImReg-1, in pre-AIDS patients are encouraging.
HIV infection and AIDS are complicated and expensive in terms of human suffering, amount of care and financial cost. Like the treatment of cancer, palliation is necessary but difficult. Between prevention and cl;re lies a complex area of management that has spawned three important therapeutic efforts: vaccine development as a strategy of management as well as prevention; antiviral therapy to p-vent the p*agression of infection; and immunorestorative therapy as a strategy to reduce the rate of progression of the disease and to prevent opportunistic infections. Vaccine development for both prophylactic and therapeutic purposes is receiving major attention, /.
W. Hadden L Director of lhr iIiltMW-
pJtrmwolc?qy Dhiow. Utduersity 01 Sottth
Florida Mediral Cortege.Tatrrpr, FL 33612. USA.
and will not be reviewed here’“. The virus has been fully described and the surface glycoprotein gp16O/gpl20 has been detailed with respect to its conserved sequences. Knowledge of viral surface epitopes necessary for binding to the CD4 receptor of helper T lymphocytes and those expressed on HIV-infected cells should provide the basis for potent synthetic vaccine formation using synthetic adjuvants such as the muramyl peptides and synthetic, detoxified lipid A. Antiviral therapy has developed in a remarkable way. Zidovudine (AZT, azidothymidine) is now licensed and widely used in the palliation of the condition of AIDS initial testing with patients; lower, less toxic doses indicates that it may be useful prophylactically in not=vmptomatic HIVpositive patients’. Many other antiviral drugs are under develop
col.Thrr.45, 348-355 32 Lin, K. M. et al. (1988) Psvrhouhenncology%,365-369
~
.
33 Schaefer, 0. (1986) in EIhrtir Drffermres in Rearfio!ts 10 Drugs nnd Xenobiolirs (Kalow. W., Goedde, H. W. and Agarwal. D. P., eds). PP. 77-83, Liss 34 Bmsen, K. and Cram, L. F. (1989) EIW. /. Clin. Phnnnacol.36,537~547 35 Suddendorf, R. F. (1%9) Pubf. Health Rep. 104.615-620 36 Kassam,J. P ,Tang. B. K.. Kadar. D. and Kalow. W. (1989) Drag Melab. Dispos. 17,567-572
ment (e.g. 2’,3’-dideoxyinosine and 2’,3’-dideoxycytidine or under study (2’,3’-dideoxythymidine, etc.; see Ref. 5). The notion that companion viruses (e.g. EBV, CMV, herpes virus-6, HTLV-1) are critical in the acceleration of the development of AIDS in genera! and Kaposi’s sarcoma in particular has spawned a number of antiviral approaches in which zidovudine treatment is combined with acyclovir, ribaviran or AS-101’. Although these approaches offer hope that longterm nontoxic antiviral therapy may be possible, zidovudineresistant viruses are increasingly being detected. More sensitive detection techniques indicate that the number of T cells infected in HIV-positive patients is higher than previously thought (i.e. 0.1~1.0% versus 0.01% of T lymphocytes’). This emphasizes the fact that a single transcript of the virus dooms the infected T cell even though other induction events are required to yield viral replication. Since transcription has already taken place, the ultimate fate of the virus is not affected by a reverse transcriptase inhibitor like zidovudine; other antiviral therapies, even those acting at subsequent steps of viral replication, will therefore prove ineffective in eradicating the virus. The only means known to eradicate a virus is through the immune response, and this is the focus of this review: immunorestorative therapy in HIV disease. Although their relatij-e importance and detailed mechanisms are not known, neutralizing antibody, antibody-dependent ceflular cytotoxicity, cytotoxic T cells and natural killing mechanisms are thought to be the four key factors in defense against HIV and
TiPS - March 1991 [Vol. 121
AIDS: markem and drugs The human immunodeficiency virus (HIV)is the cause of the AIDS epidemic. This blued-borne virus is transmitted through contact with blood or semen of infected individuals. On entry to the body, it binos to the CD4 molecule on the surfaceof the major subset of thymus-derived lymphocytes cakd T belpcr lyrnphocytes. It enters and becomes latent within the T lymphocytes.immunity to the virus develops involving antibody and cytotoxic CM+ lymphocytes. Antibody-
coated viruses may enter other c4s like macmphages and glial cells, by binding to their surface immunoglobulin receptors(F&s). Thus despite the presence of the immune response, the virus replicatesto infect other CD4+ and Fc+ cells. Following a long latent period, on average ten years, the progressive loss of CD4+ T lymphocytes results in an inversion of the normal 2: 1
its companion viruses as well as the other opportunistic pathogens that invade as a result of the immunodeficiency. The immunotherapy of AIDS Immunotherapy in AIDS at the end stage of HIV infection was
predicted to be an unsuccessful strategy*, and a number of subsequent reviews of the collected studies’*“’ document the fulfilment of this prediction. Immunotherapy in the absence of con-
current antiviral therapy in AIDS has not been effective in reversing the immunodeficiency. Two preparations of interferon-n (IFN-a; Schering and Hoffman-LaRoche) have been licensed by the Food and Drug Administration (FDA) for treatment of Kaposi’s sarcoma. IFN-a is effective alone (20-40% major response rates) and in conjunction with zidovudine (>60% response rate”), but it does not reverse immunodeficiency. Also, uniike the anticancer chemotherapy generally employed in AlDS-independent Kaposi’s sarcoma, it is not immunosuppressive and has not been proven to reduce the incidence of infections. Various types of transplantation techniques have been attempted: ?? Bone marrow transplantation is a widely used treatment for severe combined immunodeficiency (SCID) and certain forms of leukemia. While it is expensive and is associated with high morbidity, in these diseases it can be curative. By contrast, its use in AIDS has been generally unsuc-
cessful .
A recent reporP
using bone marrow transplantation plus zido??
ratio of helper (CM+) to supprewor/cytotoxic (CDe’) lymphocytes. This is associated with dtnical hnmunodeficiency, with the developmart of suswptibillty to infections and malignancies such aa Rapooi’s nreoma. During the final phase of the fllneaa (AIDB),the virus andviralantigenslikepllappearintherkubt&md Sgum mar+ of fympboid inktion like &mrao&Wm and neqfuin increase, indiathtg a poor
Prognosis Antiviral agents like zidovud@ (azidothymidlne; AZT) inhibit vfraf repfication but do not em&ate it. Zidovudine effectively slows the pmgma&m of the
final phases cf AIDS and also slows the pmgmasion from pm-AIDS to full-blown AIDS. Toxicity and cost limit its use. &ny ahematives and complementary forms of therapy are under study.
vudine claims success in eradicating virus, but conclusions are premature since the patient died and long-term follow up was impossible. ?? Transplantation of thymic tissue and adoptive transfer of heterologous lymphocytes has been unsuccessful in AIDS”. a Ex vivo expansion of autologous lymphocytes with interleukin 2 (IL-2) and zidovudine is under study and theoretically may offer some palliation, if economically feasible. e Adeptive transfer of virus-inactivated serum from individuals with high titer neutraiizing antibody against HIV is another approach being tested6; preliminary results indicated reduced p24 antigenemia, increased CD4+ T lymphocytes, and apparent improvement in the clinical status of a number of the patients. Intravenous immunoglobulin therapy is generally considered to be useful and nontoxic in the treatment of pediatric AIDS patients for the management of bacterial infections. A multicenter phase !I! tria! with zidovudinc in 250 patients is underway to confirm this widely accepted but unproven notion’. A number of anecdotal reports indicate that such therapy may improve the course of AIDS and Art?+related complex (ARC) in adult patients and a multicenter trial has been initiated to test this using intravenous immunoglobulin therapy alone and in combination with zidovudinet3.
Ir.iti;i! studies with recombinant IL-2 in AIDS were negative’+“; however, with persistent i-v. in-
fusion of high doses, lymphocytosis without enhanced viral recovery was observed. Toxicity is associated with a ‘flu-like’ syndrome, fluid accumulation, and increased bacterial infectiorts. A number of combined IL-2 and zidovudine phase I protocols are in progress. Schwartz et al.” treated several AIDS patients with this combination: preliminary data indicated that the combination is compatible, that the toxicity levels are acceptable and that the ability of IL-2 to inorraK CD4+ T-cell counts and cehlat cytotoxicity, and to enhance &in test reactivity was not parented by zidovudine. No increase in vial antigenemia or viral recovery was observed. The authors condude that further study is warranted. A number of trials of combined immunotherapy and antiviral therapy are in progress in AIDS patients. However, the ensuing discussion should make it clear why relatively little can be expected. Immunorestoration &I ARC and
asymptontaticHIVi&ction IFN-ar modulates various immune responses. Thus it enhances killer .cell activity by lymphocytes, mac@tages and naiural killer ceBa while depressing lymphocyte proliferation and S;?cretO responses. Two recent reports’7 Jb indicate that IFN-IX treatment of pre-AIDS patients reduces HIV virus recovery, p24 antigenemia, and opportunistic infection despite toxic side-&e&s. Several combined protocoIs (IFNr?*vith diethyldithiocarbamak, see below, IL-2 or ridsvudine) are underway.
‘JWS- Marc!r 1991 IVoL 12! Am&en is a polynucleotide derivative of poly(IC) with spaced uridines to provide RNase cleavage sites. It has anti-HIV activity in vitro. It also induces interferon and acts as an immunomodulator in oivo, which is characteristic of other interferon inducers including natural killer cell activation. However, despite this activity and despite the lack of toxic sideeffects observed with poIy(lC), a multicenter, double-blind phase II study was terminated early due to lack of activityb. ImReg-1 (see Fig. 1) is a dialysed leukocyte extract from normal donors in which the oligopeptides Tyr-Gly-Cly and Tyr-Gly are thought to be the nonspecific active components. ImReg-1 modulates lymphokine production in vitro and enhances dermai skin test responses in uivo when given intracutaneously with tetanus toxoid antigen. In a multicenter trial” totaRing 141 ARC patients, 93 were treated with SmReg-1 bi-weekly and showed a significantly reduced tendency to progress to a clinically relevant endpoint (4.3% versus 25%) or to AIDS (3% versus 17%). Marginally significant changes in CD4+ counts and symptom scores were also observed. No toxicity was observed. A larger confirmatory trial is planned. Methyldithiocarbamate (OTC) jlmuthiol) is an orally active thymomimetic drug that is more active and less toxic than its predecessor levamisole’s, Multicenter controLled studies1950 in 143 symptomatic pm-AIDS patients indicate that OTC decreases symptoms and AIDS conversion (13% to 4.5%) and tends to increase CD4* lymphocytes. Kaplan et aLa reported that decreased lymphadenopathy occurred in most patients with CD4 counts greater than ZOO,in a small randomized controlled trial. These findings have been extended in a large multicenter study of AIDS and ARC patients heated orally with 400mgm-2 OTC weekly, where 389 patients showed a significant (-50%) reduction in opportunistic infections in both AIDS and ARC subjects=. Although the number of T cells expressing CD4 increased in he MT-treated group (255 to 30 mm-‘), they did not decline, as had been exwcted, in the control
group (unchange\; at 270 mm-‘); the changes were, therefore, not significant. No significant toxicity was observed. A 1600-patient trial is in progress in Europe to determine the effect of DTC on asymp tomatic HIV-positive patients. Isoprinosine, an inosine-containing complex, is a thymomimetic drug that induces T-cell differentiation and promotes Tcell function in oitrs and in aivo’s. lnitial controlled trial!?’ demonstrated significant increases in CD4 counts and natural killer cell activity and significant decreases in symptoms. Fewer cases of ARC converted to AIDS in patients with progressive generalized lymphadenonathv and mean CD4 counts greate; th& 500 mme3. Several multicenter doubleblind triafs have been completed. In the USA a trial of 696 HIVpositive symptomatic patients with CD4 counts less than 400 mmv3 did not reveal significant immunological or clinical results (see Ref. 6). By contrast, a Scandinavian trials with 8(56Hlv-positive symptomatic ARC patients with mean CD4 counts greater than 425 showed a significant reduction in ARC to AlDS conversion (4% to 0.5%) over a six month period, although no significant immune correlates were obtained. tn Italy, from a trial with 553 asymptomatic HIV-positive iqlividualsx+, isoprmosine treatment -wdb8ssociakd with no new infections; 12 controls developed infections. In this study, decreawd symptoms, preservation
of 08 ratios and an increase in natural killer cells were observed in the treated group. No toxicity was observed. These studies indicate that isoprinosine treatment benefits HIV-positive patients by preventing the development of infection only when CD4’ lymphocyte counts are greater than 400 mm-‘. Thyrnopentir. is the pentapeptide active site of thymopoietin, a chemically defined thymusderived peptide having thymomimetic activitv irr vitro and in viuo. Initial co&roRed studiessr2B with thymopentin showed positive effects. On the basis of these findings, a blind multicenter tintrial- involving 47 thymo treated asymptomatic H Jen-positive and ARC patients and 44 placebo-treated controls was set up. Preliminary results indicated that four controLs m to constitutional symptoms or AIDS, while none of the treated patients progressed (p
TiPS - March 1991 Wol.
110
results from
,_-?__ tidovudine therapy t----
?
?
t
0
immunotherapy . . . . . . .)
2
4
6
3
10
12
14
Years fig. 2 Therapymodelh7rHIV intec/iim. current status of immunorestontive therapy The most useful therapeutic approaches oriented toward improving the function of T lymphocytes in HIV disease involve two drugs, DTC and isoprinosine, and two peptides, thymopentin and ImReg-1 (Fig. 1) for use alone or in combination with antiviral therapy. No significant side-effects with these agents have been noted; thus they are safe and no incidence of HIV activation has been uncovered. Their combined use with antiviral agents relies on the assumption that the antiviral agent8’ do not inhibit their activity. This remains to be determined. The total number of reported patients treated with these agents exceeds 2500, which underscores the statistical significance of the findings. The case for lmmunotherapy is no longer in doubt. The question remains as to how to perfect it. Figure 2 offers a schematic view of the current use of immunotherapy, which in this context would be nore appropriately termed ‘post-infection immunoprophylaxis’. The length of the latency period is variable, presumably related to other concomitant immunosuppressive influences. Zidovudine treatment should be reserved for AIDS itself. Its eartier use may or may not ultimately be fruitful in terms of prolongation of life, because of the risk of Development of HIV resist-
ance. Combined use of zidovudine or other antivirals with immunotherapy based upon the experience with isoprinosine, DTC, ImReg-1 and thjiinopentin appears to be beneficial when CD4 counts are greater than 4OGmmm3. A more detailed analysis of lymphocyte dysfunction in early HIV infection is warranted to determine the effects of soluble serum-borne inhibitors on Tlymphocyte function. Conceptually, it will be relevant to introduce immunotherapy at a point before the deve!opment of poor prognostic indicators in asymptomatic HIV-positive individuals, e.g. p41 antigenemia or elevated neopterin or a-microglobulin levels. In early HIV infection, before the onset of AIDS, the initial incidence of infected CD4 lymphocytes was previously thought to be extremely low (1: 1OooO)and even with recent estimates of the frequency of HIV transcript-bearing CD4+ cells (0.1-l%) the degree of immunosuppression in early infection is out of proportior. to the frequency of cells affected. When CD4 lymphocyte counts are corrected for in vitro tests of lymphoproliferative responses, the degree of functional impairment is also out of proportion to the loss of CD4+ cells. Thus, a large number of lymphocytes are dysfunctional. This ‘pan anergy’ i.e. a general defect in cellular immune function - presumably
121
retrovirus-induced
or -protiuced immunosuppressive factors and/or autoantibodies to T cells. Clarification of these factors and their mechanisms is needed. The molecular strategies to augment T-cell function with thymomimetic agents in pre-AIDS appear to depend on the presence of lymphocytes whose function, when restored, will benefit the host and not result in the activation and spread of virus. Ideally the system should be replenished with virus-free T lymphocytes produced by the thymus. The thymus involutes and eases fc function relatively early in life and thymic secretory capacity for thymic hormones declines in midlife at a time corresponding to female gonadal menopause. Thus, many conclude that the thymus is nonfunctional. However, studies of radiation injury, cancer chemotherapy, and bone manow transplantation for leukemia indicate that the thymus can pmcess precursors to restore the T-&l system in the periphe$l. It appears that when the need arises, signals develop to induce thymic T-cell processing function. These signals have not been identified, but recent evidence implicates both interleukins and pituitary factors (see Ref. 10). The thymus is destroyed in AIDS with obliteration of both epithelial and lymphoid components. Once the thymue has been deshoyed, T cells cannot be generated anew. It is not clear at what stage of HIV infection the thymus loses its capacity to replenish. Obviously, the administration of thymotmphic substances to enhance T-cell replenishment should logically precede thymus destruction. A useful therapeutic s&&w would be to employ thyrnic and pituitary hormones, and interleukins, to stimulate T-ceJl development provided that a residual, marginally functioml thymus still exists. In the context of HIV infection, this therapy would include antiviral therapy. Cl
cl
Cl
Immunorestorative therapy per SC has not proven useful in fully developed AIDS. EN-u alone and in conjunction with zidovudine is usetul in the m Kaposi’s sarcoma inaYznzto;! Al tive immunotherapy with Lv. im-
TiPS - Mnrch 2991[Vol. 121 munoglobulin, high titer anti-HIV sera, and ex viuo IL-2-expanded T lymphocytes all remain realistic approaches alone and in conjunction with antiviral therapy, Marrow, thymus and lymphocyte transplants alone have not proven useful. The thymomimetic drugs isoprinosine and DTC significantly reduce disease progression and infections in large trials of H!V-positive pre-AIDS patients, particularly when CD4+ lymphocyte counts are greater than 400 mms3, and licensing seems warranted. Preliminary data with the thymominetic biologicals thymopentin and ImReg-1 suggest that their use in conjunction with antiviral therapy before the onset of AIDS may be helpful. Recent work on the important HI? surface epitopes for neutralizi?tg antibody and cytotoxic T cells makes possible new therapies with human monoclonal neutralizing antibody and synthetic vaccines to manage disease. Also, recent developments on the important intrathymic regulators (thymic hormones and interleukins) as well as extrathymic regulators (pituitary hormones and interkukins) make possible more complex strategies to improve T-ceil number and function. While cure at this point seems out of reach, combined therapies ative atints, and antiviral therapy offer the best prospects for enforcing viral latency and sustaining healthful, productive ezistence of those infected.
Referenles 1 Ada.*;. (lsw) Nofure 339,331-332 2 Bologesi, I?. P. (1989) S&arc 246, 123% 234 3 Girafd, M. (‘9%). Cancer Dclecf. Preu 14,411413 4 Volberding. F. A. et QL (1990) N. EqI. /. Med. 322,941-q 5 dcclcrq. ‘c. :199m 7.cnds PlturQlnco/. Sri. 11,1%205 6 Abmmr, D., Grieco, M., Cottiieb, M. and Bpeer, M., edr (1989) AIDS/H/V Erpnimrnfaf Tw&mwf. AMFAR Dirertory (Vol. 3, bio. 1) 7 Ho, D. D., Moudoil, T. and Alam, M. (1989) N. Et@. /. Mrd. 321,1621-1625 8 Hadden, J. W. (1984) in Ann. NY Acad. Sri. Vol. 437 (Belikoff, 1. J., T&stein, A. and Him&man, S. 2, ~45). y. 16-87, Hew York Academy of Sciences 9 Hadden, J. W. (1987) In AfDS Qrd Ofkcr MQ@rs&tiorts of HIV h&x-lion (Womuwr, C. P., Stahl, R. E. and Bottone, E. J., edr), pp. 992-1017. Nyes Publications
111 10 Hadden. J. W. (1989) in Aduances br lnrnruaopltlrrmacdogy 4 (Hadden, J. W. et d., ds), p. 19, Pegamon he55 11 Lane, H. C. (1989) AIDS 3 (Suppl. 1). 181s-185s 12 Holland, H. K. et Ql. (1989) Aafl. Inhrn. Mrd. 111.o~981 13 DeSimone, C. tr a! (1990) J. Clbr. Lab. Anal. 4.313-317 14 Schwartz, D. H., Skowron, G. and Merigan, T. c. Pmt. Sixth bt. con\. on AfDS, San FrQnciscoSB444 (abstr.) 15 Davey, V., Johnson, R. P. and Lane, H. C. (1989) Pm. Fifth hf. Con/. O” AIDS, Morrtreal W.B.Y 322 (absh.) 16 Brook, M. G. et al. (1989) Lance!i, 42 17 Gottlieb, A. A. et Qf. (1988) Proc. Folrrth Inf. COflf. O)I AIDS, Sfockholm 3048 (abstr.) 18 Hadden, J, W. (1985) in Syraposiumon Imm0Q0pkarmac0l0gy. Serc;;o Symposium (Miescher, P. A., Bolis, L and Chiooe, M., eds), pp. 183-192, Raven Press 19 Lang, J. M. rt al. (P-188)Lancr: ii, 702-706 20 LankJ. (1989) PIUC. Fifth M. Goof. O” AIDS, Moewtel W.B.P. 296 (abatr.) 21 Kaplan, C. S., Peterson, E. A., Yocum,
D. and Hesh. E. M. (1989) Lift St?.45, ...
I,,-IX 22Hersh, E. M.
ef 01.1. Am. Med. Assoc. (in
p55)
23 Clasky. A. I. and Gordon,]. (19%) Myth. Find. Exp. Clio. PhormQrol. 8, 3w 24 Bekwi, J. G.. Tsang, P. H., Wake. J. 1. and Roboz. I. P. (1987) /. Cfia. Lnb. Immmml. 24.155-161 25 Pedrrsen, C. tt al. (1990) N. Egl. /. Med. 322. X57-1763 26 DeSimrme, C. rt al. (1988) Mrd. Onr0l. Tumor Phormacothcr. 10.2~9-303 27 bcellini. W. et al. (1987) C/in. Exp. lmmunol.67.537-543 28 Silvestris, F., Gemone, A., Frassanito, M. and Dammacco,F. 11989)J. Lab. Clia Med. 113,139-w 29 Conant, M. A., Goldstein, G., Hirsch, R. L., Meyerson, L. A. and Kmmer, A. B. (1990) J. Cell. Biochem. (SuppI. 14D.148) UCLA Symposhrm on MoltcnlQr ond Cell Biology, San Francisco AIDS Meeting (abstr. L411) 3@ LUSttt. M. 1. C! Qr. (1989) TOo:iiO/. Aopl. PJIQ~QCOI. 101,32&339 31 Kelley, K. W. et al. (1986) Proc. Nat! Acad. Sri. USA 83,566~5667
.
The role of neuropeptideY In cardiovascularregulation Philippe Walker, Eric Grouzmann, Michel Burnier and Bernard Waeber Neumpeptidc Y (NPYJ is a 36 amino acid prptide present in the brain, the adrenal medulla and peripheral sympathetic nerves. The localization and mode of release of NPY led to the pmposal that this peptide plays an important mJe in modulating the contribution of the sympathetic nervous system to blood pressure control. In this paper Bernard Waeber and colleagues review the current knowledge about the mechanisms involved in NPYsignal transduction and the different mechunisms whereby NPY, released by the peripheral nervous system, may infJuence vascular tone and cardiac func!4n1.
Neuropeptide Y (NPY) was isolated for the first time in 191)2from porcine brain by Tatemoto’. It has since been the subject of numerous biochemical, physiological and pharmacological studies. This 36 amino acid peptide is a member of a family of structurally related peptides including peptide W (PYY) and the pancreatic polypeptide (PP). NPY is widespread in the central and peripheral nervous systems and is one of the most abundant neuropeptides found in the mammalian brain. Moreover, its amino acid sequence is remarkablyconserved P. WQfkrr nod E. Crownm~~r are Resrwch ASSOciQkS nod M. 6lwnier ead g. WfftbcrQrr r\ssistaat~ro@son in thr Diuisioaof Hypwfrnsior, Cwtrc HospWrr Uniwsffair~ VQQdois. 1011 L~rsnnrc, Swifxrlatld.
across species. NPY exerts a multitude of actions, both centrally and peripherallyr3. This review describes the peripheral actions of NPY that might participate in cardiovascular regulation. Localizatkm and release of NPY The development of anti-NPY antibodies has allowed the peptide to be localized using immunohistochemical techniques. NPY is present most abundantly in the perivascular nerve fibers of many organs, in pardcular around the cerebral, renal, coronary, mesonteric and femoral art&esU. In general, NPY-con:aining fibers are more abundant amund arteries than veins. Fibers around small arteries show mom immunoreactivity than nerve fibers around large