Nonspecificdefencemechanism: the role of nitric oxide F.Y. Liew and F.E.G. Cox There is a marked contrast between the extraordinary complexity and specificity of th e a d ap twe immune response and the limited number of effector mechanisms that it can direct. Recently, a great deal of interest has focused on the possible role of nitric oxide (NO) in one of these mechanisms. Here F.Y. Liew and Frank Cox examine the evidence supporting a role for NO in parasitic disease and suggest possible mechanisms of NO-mediated parasite damage. If, as has been postulated, the immune responsehas evolved to combat invading organisms’, then parasites, particularly parasitic protozoa, have been remarkably adept at taking advantage of the cell-mediated responses directed againstthem. A number of protozoa inhabit and multiply in the cells of the immune system: T6eileria spp are unique in that they inhabit lymphocytes’, Toxoplasma gondii are found in neutrophild and several species,including T. gondii, live in macrophagesfor the whole or part of the life-cycle in their mammalian hosts. Parasitic p&ozoa gain accessto resting macrophages in many ways and, once inside the host cell, each has its own way of surviving the battery of attack mechanisms, including enzymic and pH-dependent processesand reactive oxygen species,mounted by theseprofessionalkiller cells’. Leishmaniu spp can survive within the fused phagolysosome; Trypanosonu cruzi escapesinto the cytoplasm and T. gondii, which enters the cell via a nonphagocytic mechanism, inhibits lysosome-phagosome fusionj. Avian malaria parasites also multiply within macrophagesand mammalian malaria parasites must transverseKupffer cellson their way to the liver but in neither of these casesis the mechanismof survival understood. Macrophages, therefore, provide a safe habitat for those organismsthat have evolved the ability to circumvent attack but, once activated, thesesafehavensbecome the most hostile of environments and parasitesthat live in macrophagesare potentially subject to attack from a variety of mediators. Such parasitesare therefore living on a knife edge, always having to avoid activating the cells they inhabit. However, as macrophage activation can be independent of the parasite, destruction can be brought about by mechanismsthat can be regarded as nonspecifi&. Nonspecific immunity The concept of nonspecific immunity dates from the work of Coley who developed ‘vaccines’ consisting of killed bacteria (Coley’s toxins)’ which brought about the regressionof establishedtumours in humans and mice. With the introduction of chemotherapyand radiotherapy, this work was abandoned but the concept was resurrected in the 1950s with the discovery that BCG could protect animalsagainst a range of bacteria and tumoursX and recently it hasagain beenargued that BCG might be

used as an immunopotentiator in parasitic infections’. One of the problemsinherent in the useof BCG is that it is a live vaccine and considerableeffort has been put into identifying bacterial products that are equally effective. By the 19SOs,a number of microorganisms (including Corynebacterium parvtm, Listeria monocytogenes,Brucella abortus, Bordetella pertussisand Salmonella spp), various bacterial extracts (including mycobacterial cell walls and lipopolysaccharide (LPS)) and synthetic analoguesof bacterial cell walls (suchasmuramyl dipeptide) had been shown to be potent stimulators of nonspecific immunity’“. Theseorganismsand substanceswere usedby different workers in different ways, somebelieving that they were a panaceafor numerousills, while others were convinced that they would throw light on unexplained aspectsof the immune response.BCG could not only protect against tuberculosis and leprosy but, under experimental conditions, it was also remarkably easyto induce nonspecific immunity againsta number of microorganisms.BCG and several microbial products were found to protect mice against the macrophage-inhabiting protozoa T. gondii, Leishnzania spp and T. cruzi and against the blooddwelling protozoa, Plasmodium spp and Babesiaspp”. The whole concept of this nonspecific immunity now needsto be reassessed as it has gradually become clear that host responsesto microorganisms and microbial products are highly specificin their initiation and involve the induction of cell-mediated immune responsesdirected against the antigenic epitopes recognized in the first instance. However, the effector mechanismsare largely nonspecificand unrelated organismsmay become ‘caught in the cross-fire’ if, for example, they inhabit a cell suchasa macrophagethat hasbeenactivated or come into contact with the products of such a cell. Although the key to many anti-protozoan defence mechanismslies in the activation of macrophages,it is not known how thesecellskill parasites.Experimentally, there is an apparent synergismbetween two signalsthat operate sequentially, one a macrophageactivation factor and the secondusually suppliedby a bacterial cell wall or cell wall component, such as LPS”. A number of cytokines can provide the first signalbut there is no doubt that a central role is played by gamma-interferon (IFN-y), a moleculethat hasbeen implicated in virtually every parasitic infection 13. Thus a major protective

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nonspecificdefence Since then, NO release has been on macrophage+“‘. shown in many tissues”. To immunologists, the most citrulline NO exciting feature of NO is its inducibility in the endothelial cells and leukocytes following stimulation with TNF and IFN-y. When incubated with IFN-y in combination with TNF-a, interleukin I (IL-l) or LPS, murine endothelial TNF, interferons and endotoxin cells generate NO”. also stimulate NO production by macrophagcs, neutrophils, Kupffer cells and hepatocytcs’“. These findings NOI L-arginine have important implications for host defence mechanL-IVMMA isms against infections. One of the clues that led to the discovery of the formation of NO by vascular endothelial cells came from work on macrophages”. Macrophages produce nitrite (b) NO. + enzyme[4Fe-6] - enzyme (NO,-) and nitrate (NO,-) (Ref. 28) which are derived from L-arginine, and their production is blocked by \,A \N=O structural analogues such as N’,-monomethyl-L-arginine NO has now been shown to be syn(L-NMMA)~~,“‘. thesized from one of the terminal gunnidino-nitrogen (c) 0;. + NO * - ONOO- + H+ + ONOOH atoms of t.-arginine- Il-.ij, The enzyme responsible for NO synthesis (NO svnthase) is cytosolic, NADPH-dependent - HO. + NO,. NO; + H+ and leads to the formation of stoichiometric amounts of I.-citrulline and NO (Refs 29 and 34 and Fig. I). It is now clear that there are at least two distinct isoenzymes; the Fig. 1. The generutiorl o/NO urrd the possible me&~~isms ofits oh-rrlicrobiul constitutive enzyme responsible for basal NO ssnthcsis effects. (a) NO synthesis is cutulysed by NO sytkase md is selectively md cm in both the endothelium and the nervous system Is Ca?+be competitively bhbited by a11r.-urghine urralogrre, I.-NMMA. (6) NO rorrld dependent, wherea; the cytokine-inducible enzyme is react with the Fe-S grorrps formiq utf irorr-tiitrosyl cmples rurrsirrg the Ca’+-independent. This finding suggests that it may be imctiuutiorl und degrudatiofr of the Fe-S prosthetic grolrps of acorlituse md induced NO corvplex I md complex II of the rvitocborhia electrorl trumport chui~r (Refi possible to modulate the immunologicallv manifestation without affecting the const;tutive, house26,61,62). (c) Alternatively, NO my react with 0,-e to form ONOOwhich decqs rapidly once protorlated to form the highly reactive HO. . keeping NO functions. It has been known for many years that microorgnn(Data from Ref. 63.) isms, or microbial components, can increase host resistance to the growth of turnours: by 311 antigen-specific mechanism involves the induction bv IFN-y in conjuncstep” that involves sensitized lymphocvtes and by a tion with other cytokineslq, of various low molecular nonspecific step that is mediated by aciivated macroweight and potentially toxic factors. IFN-y is not toxic on phages-‘h-‘s. Sensitized Tcells produce lymphokines such its own and the search for an effector molecule focused as IFN-y that activate macrophages to lyse tumour cells on tumour necrosis factor cx (TNF-(Y), which has been nonspecifically’” but this process requires a second signal implicated in a number of parasitic infections”. The role supplied by LPSd” and cell-cell contact between macroof TNF, ilr ho, is not at all clear. In general, while it is phages and target cells -II. More recently, it has become active, in vitro, it frequently turns out not to be toxic, itl apparent that this nonspecific tumour cell killing activity viva, suggesting that it synergizes with other cytokines’“. is mediated by NO derived from I.-arginine’“. Since It has been proposed that IFN-y produced by T cells similar macrophages can be derived from mice infected activates macrophages to secrete TNF which in turn with various intracellular pathogens, it may be expected sensitizes the same or other macrophages to secrete reacthat the NO effector pathway also inhibits the multiplitive oxygen species that rapidly destroy parasites through cation of such pathogens. Macrophages activated with a process of lipid peroxidation”. However, this explaIFN-y plus LPS h ave a powerful cytostatic effect on the nation is not entirely satisfactory. For example, reactive fungal pathogen C~~~ptococcrrs ~wofo~~~w~~s~~ and the oxygen intermediates can destroy rodent malaria paraprotozoan T. goi~/i?‘, the microbiostatic effect being sites but mice deficient in activated macrophages are also dependent on L-nrginine and inhibited by L-NMMA. able to do soIs. These and other observations suggest that NO has also been shown to be important in other alternative mechanisms may be involved and attention parasitic infections and has been most extensively studied has turned recently to the potential role of NO. in leishmaniasis. Mouse peritoneal macrophages stimulated, in vitro, with IFN-y in the presence of LPS arc The biological role of NO efficient in killing Leishania and this leishmanicida In 1987, Furchgott” and lgnarro”’ independently activity can be completely abrogated by L-NMMA in ; suggested that endothelium-derived relaxing factor dose-dependent manner, but not by its u-enantiome (EDRF) was either NO or a NO-related molecule. The (D-NMMA)“~-~~. Furthermore, culture supernatants o first direct demonstration of the release of NO by mammacrophages activated by IFN-y contain significantly malian cells was in the vascular endothelium where it increased levels of NO,- (Refs 46-48), the production plays a role in the control of vascular tone and platelet of which is also inhi&ed by L-NMMA”~.“~ (Fig. 2: aggregation”J1. This had been implied in earlier work L. major promastigotes are killed when incubated, i,



nonspecificdefence (a)

2.0 -

(b) 800 -


+ o-NlvlMA

1.5 -

600 -

+ D-MvlMA








Fig. 2. The itzhibitiotr of (a) tnacrophage leishmanicidul activity peritoneal macrophages treated with /FNq and TNF-u (open J/one (open circle). Macropbage leisht~~atricidal activity was tneasured by the accumulation (72 h) of NO?- in the culture I.-NMMA (closed circle) in a dose-dependent tnanner





L-NMMA / o-MvlMA



and (6) nitric oxide generation by I.-NMMA and D-NMMA. Starch-activated murine triangle) are highly leishtnanicidal compared with tnacrophages treated with medium tneasured by the incorporation of ‘[H/-thymidine by residual parasites, and NO was supernatant. The leishtnanicidal activity and the generation of NO were inhibited by but were not affected by the D-NMMA (closed triangle). (Data from Ref. 53.)

l&o, at room temperature in phosphate buffer saline containing NO 4c. The importance of NO, in viva, is demonstrated by the finding that disease in CBA mice infected with L. major is exacerbated when L-NMMA is injected into the lesions resulting in a IO-‘-fold increase in the number of parasites that can be extracted from the lesio& (Fig. 3). TNF-a together with LPS can also activate macrophages to kill intracellular L. 171t7jor’~~~” and the leishmanicidal effect is directly correlated with the release of NO”. Furthermore, TNF-a can synergize with IFN-y in inducing macrophage leishmanicidal activity”qYJ and this activity, together with NO production, can be completely inhibited by L-NMMA but not I)-NMMA’j. The mechanism for the synergistic effects of TNF-cx and IFN-y in this system is unclear but the two molecules also synergize in activating macrophage cytotoxicity against TNF-insensitive target cells4’~4x~54-5’. Interestingly, IFN-)I enhances the TNF secretion by LPStreated monocytes- ‘b.’ The presence of LPS is essential for the consistent activation of macrophages by IFN-y and TNF but, again, the precise role of LPS is unclear although it may be providing some form of priming signal for the activation pathway. Lymphokine-activated macrophages are also cytotoxic for the larval stages of the helminth Schistosotna [email protected], the killing being L-arginine-dependent and inhibited by L-NMMA h0. Nitrite was detectable in the



10 -



Fig. 3. Effect of a specific NO inhibitor on the disease developtnent in tnice infected with L. major. Croups of CBA tnice were infected in the footpad with 10’ L. major promastigotes and, starting from day 6 post-infection, injected daily for six consecutive days with 5 mg of L-NMMA (open circle) or D-NMMA (closed circle) in 20 ~1 PBS or PBS alone (closed triangle). Disease development was estimated by measuring the footpad thickness or the number ofparasites in the lesions. Figures in parentheses represent the log,,, dilutions of culture at which viable parasites are detectable in the footpad at day 20 post-infection. (Data from Ref. 45.)






Pathogen/ antigen

1 (1) 00 *t-0 Macrophage T cell

gerous unless carefully controlled. Reactive oxygen intermediates, such as superoxide, cause vascular endothelial damagehx, TNF is largely responsible for the pathology associated with malariahy and nitric oxide can profoundly affect blood pressure and flow’(‘, inhibits platelet adhesion and aggregation” and is involved in some autoimmune disease models (F.Y. Liew, unpublished). However, a clear picture of the regulatory mechanisms involved in both protection and pathology is now available and this understanding will greatly facilitate our ability to devise methods for therapeutic intervention against infectious as well as autoimmune diseases. This will undoubtedly be accelerated by further knowledge of the molecular nature of the enzyme NO synthase.

Conclusions Recent studies have clarified much of the mystery of nonspecific immunity. The sequence of events can be summarized as follows (Fig. 4): (I) deliberate immunization or infection leads to sensitization and clonal expansion of T cells through the normal antigen-processing and antigen-presentation pathways; (2) T cells secrete culture supernatant of the Inrvicidal, activated macro- lymphokines such as IFN-y as a result of such activation phages but not in the nonlnrvicidnl culture containing and then moreso following restimulation with persistent, specific antigen or on reinfection; (3) IFN-y activates t-NMMA. macrophages to produce other cytokines such as TNF-a and IL-1 that, together with IFN-y, can induce macroMechanism of NO-mediated killing The mechanism of the NO-mediated nonspecific kill- phages to eliminate nonspecific tumour cells and pathoing of tumour cells and pathogens has yet to be clarified. gens; and (4) the mechanism of these macrophage funcSeveral workersl”.hr,hZ have postulated that NO reacts tions involves, at least in part, nitric oxide. with Fe-S groups, resulting in the formation of ironThe relative role of oxygen metabolites and nitrogen nitrosyl complexes that cause the inactivation and degra- intermediates in such a system is at present unclear. In the dation of Fe-S prosthetic groups of aconitase and com- Leishrmmin and the Schistosomn models, the killing of plex 1 and complex 11 of the mitochondrial electron parasites can be completely reversed by L-NMMA-“*‘“J’” transport chain (Fig. 1b). This is supported by the finding and can proceed normally in a macrophage cell line that addition of excess iron or the reductant sodium deficient in the respiratory bursth0.71. Furthermore, the dithionite to Ivmphokine-activated macrophage culture inhibition of leishmanicidal activity is accompanied by inhibits the killing of schistosomal larvae, in vitro6”, enhancement of the respiratory burs?‘.‘“. These data under conditions that are known to stabilize the activity indicate that, at least in these experimental systems, NO of iron-containing enzymes involved in respiration. Ni- is necessary, and may be sufficient, to account for the trite production does not decrease under these con- macrophage microbicidal activity. However, it remains ditions. Alternatively, NO can react with the oxygen possible that killing of early logarithmic growth phase of anion radical Oa-. to form peroxynitrite anion promastigotes involves respiratory oxygen intermediates (ONOO-) which decays rapidly once protonated to produced by normal macrophages (not activated by form the reactive hydroxyl radical HO. and the stable cytokines) while those parasites that survive this initial free radical nitric oxide NO,. as suggested by Beck- defence (amastigotes) are destroyed only by cytokineman et ~1.~” (Fig. lc). Hydroxyl radicals are highly activated macrophages involving NO. Although the enreactive, combining with almost all molecules found zymatic pathways leading to the synthesis of reactive in living cells with rate constants of between 10’ and oxygen intermediates and reactive nitrogen intermediIOr” M-I s-l (Ref. 64). The selectivity of destruction of ates are distinct-sO, there is evidence that the end products pathogen by NO may be explained by the fact that NO can influence each other. For example, superoxide disis very short-lived (6-50 s)6i-h7. The target pathogens mutase can enhance the half-life of NOi3*” and catalase would have to be close to the source of NO synthesis. can inhibit the NO synthesis in activated macrophages However, sustained high levels of NO production (F.Y. Liew, unpublished). would also be expected to be damaging to the host It is now clear that Calf-independent NO synthase is cells and tissues. inducible in both the lung and liver of rats treated with endotoxin”. Since, in VIVO, these organs filter out infecPathological consequences of nonspecific immunity tious organisms, the host-defensive role of these organs Despite earlier hopes that the induction of nonspecific and the involvement of NO in this process may assume immunity might be a valuable tool in the fight against considerable importance. Furthermore, since infectious infectious diseases and tumours with the subsequent agents need to be killed and processed and the relevant production of immunostimulants of various kinds, it is peptides presented with the major histocompatibility now clear that such responses can be extremely dan- complex molecules for the induction of an effective Tumouricidal Microbicidal


nonspecljk defence 32 Marletta, M.A. et al. (1988) Biochemistry 27, 8706-8711 33 Hibbs, J.B. et al. (1988) Biochenz. Biophys. Res. Con7nrun. 157, 87-94 34 Palmer, R.M.J. and Moncada, S. (1989) Biocl7e771. F. Y. Liew is at the Dept of Experimental lmmcazobiology, Wellcorne Research Laboratories, Langley Court, Beck- Biophys. Res. Commm. 158,348-352 35 Zbar, B. et a/. (1970) /. Nut/ Cancer Inst. 44, 473-48 1 erzharn BR3 3BS, UK and Frank Cox is at the Division of 36 Alexander, P. and Evans, R. (1971) Name (London), Biomolecular Sciences, King’s College London, Catnpden New B/o/. 232,76-78 Hill Road, London W8 7AH, UK. 37 Keller, R. and Jones, V.E. (1971) Luncet i, 847-849 38 Hibbs, J.B., Lambert, L.H. and Remington, J.S. (1972) Nuttrre (London), New Biol. 235,4S-50 References 39 Svedersky, L.P. et al. (1984) I. E.up. Med. 159, 8 12-827 1 Mitchison, N.A. (1990) Parasito/ogy 100, S27-S34 40 Weinberg, J.B., Chapman, H.A. and Hibbs, J.B. (1978) 2 Morrison, W.I. et a/. (1986) /irrrrrrlno/. 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(1989) Free Rud. Res. Co~nrmaz. 5, 315-3 18 26 Hibbs. J.B. et al. (1990) in Nitric Oxide from t.-arpinine: 69 Clark, l.A., Chaudhri, G. and Cowden, W.B. (1989) a Bioregrdutory Systejn (Mbncada, S. and Higgs, E.A.:eds), Tram. R. Sot. Trop. Med. Hyg. 83, 436-440 PD. 189-223. Excerota Medica 70 Valiance, P., Collier, J. and Moncada, S. (1989) Luncet i, 27 Moncada, S., Palmer, R.M.J. and Higgs, E.A. (1989) 997-1000 Biochenz. Phamacol. 38, 1709-1717 71 Radomski, M.W., Palmer, R.M.J. and Moncada, S. 28 Stuehr, D.J. and Marietta, M.A. (1985) Froc. Nut/ Acad. (1987) Br. J. Phunnacol. 92, 639-646 Sci. USA 82.7738-7742 72 Scott, P., James, S.L. and Sher, A. (1985) Ezrr. 1. 29 Hibbs, JIB., Taintor, R.R. and Vavrin, Z. (1987) Scie?lce Immrrnol. 15, 553-558 235.473-476 73 Gryglewski, R.J., Palmer, R.M.J. and Moncada, S. (1986) 30 fyengar, R., Stuehr, D.J. and Marietta, M.A. (1987) Proc. Nutrrre 320, 454-456 Nat/ Acad. Sci. USA 84, 6369-6373 74 Rubanyi, G.M. and Vanhoutte, P.M. (1986) Am. 1. 31 Palmer, R.M.J., Ashton, D.S. and Moncada, S. (1988) Physio1. 250, HS15-HS21 Nature 333,664-666 75 Knowles, R.G. et a/. (1990) Biochem. /. 270, 833-836 immune response, NO may in initiating this cascade.


an important



Nonspecific defence mechanism: the role of nitric oxide.

There is a marked contrast between the extraordinary complexity and specificity of the adaptive immune response and the limited number of effector mec...
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