Immunology Today March 1982

Vaccines and infectious disease from H e n r y Metzger and Brigitte Askonas What part has i m m u n o l o g i c a l research to play in fighting infectious disease? This was perhaps the most important question articulated at a s y m p o s i u m organized j o i n t l y in Oaxtepec, Mexico, on November 8—13 last year, by the International U n i o n of I m m u n o l o g y Societies a n d the S o c i e d a d M e x i c a n a de Immunologia. Research's traditional role - that ot developing vaccines in order to prevent the development of a disease continues to be the most obvious path to follow and the one with a |3roven record of success. A recent example was detailed by Paul Holland (NIH, Bethcsda) who described the development of passive and, more importantly, active immunization to the hepatitis B virus. While the vaccine's current costs prohil:)it its widespread use, recent clinical tests stronglv support its uselulncss when given to high-risk individuals prophylactically and (in combination with passively a d m i n i s t e r e d a n t i bodies) to those known to liavc been exposed. Ckjntemporary recombinant DNA techniques make it likely that a substantially cheaper and therefore more widclv ap[)licable vaccine will be forthcoming. M. Levinc (linivcrsitv o( M a r y l a n d ) - who discussed enterofjactcrial diseases - was ho[)eful that a typhoid vaccine could be developed using a new mutant bacterial strain, and inactivated leprosv [)rcparations are also under trial. In malaria (P. Weidanz, H a h n e m a n Medical College) there is a world-wide effort to select [U'otectivc antibodies and through them to dclinc antigens which will induce protet:tion. M u c h of the meeting was taken up Ijy descriptions of how a varietv of infectious organisms - viral- bacterial

or protozoan - manage to evade immune control, whether that control is induced by vaccines or is a conseq u e n c e of n a t u r a l infection. T h e different escapee routes include molecular mimicry, intracellular replication of organisms or viruses, retention of infectivitv' in circulating i m m u n e complexes, and induction of strong immLinosup[)ression (antigen specihc or non-specific). .Sup[jressive T cells and macro[)hages have also been implicated. Certain of these mechanisms have been recognized lor many years: the ability of influenza viruses to varv their surface [)rotcins eontinuall\' and so render impotent existing host a n t i b o d i e s is a well-known example. In this particular instance - discussed bv Brigitte Askonas (National Insitute for Medical Research, London) - h u m a n [jopulations may in fact be "more i m m u n e than we think". Not only may the recurrent efjidemies be smaller t h a n is sometimes thought, because of overdiagnosis, but the morbidity they engender may be much less than W'ould otherwise be the case were it not for T-cell mediated immunity, which is crossreactive for all influenza viruses within a type. \ question that remains unresolved in this instance, as well as with .African trypanosoine infections for e x a m p l e ( K e n n e t h Hudson, Brunei University, L'.K.), is whether with persistant efforts a less \'ariable set of epitopes can be elucidated. In principle one anticipates that the same invariant structures which arc re(|uired by the organisms for invasiveness could, if identified, serve as epitopes against which protective antibodies (ould be raised. Ho\\cver, those actually dealing with such problenis were less optimistic about this a|)proach than some of the less experienced discussants! Never-

Macrophages

Heterogeneity under scrutiny M a n y kinds of ligand bind to the m e m b r a n e of macrophages. W h a t ever the stimulus applied and whatever response is examined - receptor or antigen expression, cytotoxicity, secretion, phagocytosis, locomotion it has become plain that not all macrophages respond to the same extent and that some do not respond at all. T h e origin and significance of this heterogeneity was a recurring theme during the first few days of the Reticuloendothelial Society's 9th International Congress in Davos, Switzerland, last month. Macrophages are currently considered to differentiate from bonemarrow precursor cells via circulating monocytes. T h e r e may be several, perhaps many lines of descent or just one, cells differing in function because they differ in maturation, .'\nswers to this question have been sought by dividing up macrophage populations physically (by size or density) and functionally (e.g. rosetting v. nonrosetting cells) and several refinements to these approaches were discussed at the meeting. But the strongest hopes for a solution lie in studies of the macrophage surface with monoclonal antibodies. By this means a 160 kD protein has been identified in mice which is expressed by resident and activated peritoneal macrophages, blood monocvtes, adherent spleen cells and alveolar macrophages but not by dentritic cells or other leucocytes. It is absent from macrophage p r e c u r s o r s in b o n e marrow a n d appears only as the cells mature. But its expression is modulated by the stimuli the cells receive: although still detectable on activated macrophages, the antigen is diminished in quantity (•dov\m-rcgulated") on these cells as they respond to infection in nni with (ja,i,i „„/,. :v

58

Immunnlngy Today, vtil. 3, .\'a. 3. J9S2

Vaccines and infectious disease - i'i>u/'l. [run: /(..)/ protein synthesis (which by itself was

Heterogeneity under scrutiny -

thclcss, the extraordinary rai)idity with which the Kdhler—Milstein h y b r i d o m a technoloi^y is b e i n g apphcd to the |)robiem of antigenic analysis (described by almost every sjoeaker in the symjjosium) suggests that the possibility of finding such 'Achilles heel' determinants will be m u c h b e t t e r in t h e n e a r future. Another j)roblem in vaccination is that i n a c t i v a t e d vaccines do not i n d u c e protective i m m u n i t y w h e n acquired resistance is due to cellmediated responses. This was pointed out by Sheila Lukehart (U.SPHS Hospital, Seattle) in regard to syphilis, but holds true in many other infective agents. Viral infections in general terms were discussed by M . B. Oldstone (Scripps Clinic and Research Foundation). Despite the complex i m m u n e network and some non-specific responses (NK cells, interferon production a n d a c t i v a t e d m a c r o p h a g e s ) , some viruses can evade host responses and cause a persistent infection. T h e r e are a n u m b e r of reasons for this, such as the circulation of imm u n e complexes in the absence of virus neutralization (e.g. lymphocytic choriomeningitis) or the presence of viral nucleocapsids within cells without viral protein expression on the cell surface (e.g. measles), as well as the host genetic background plus i m m u n e response genes. Rotaviruses are a major cause of gastroenteritis and Romilio Espejo (Institute Investigaciones B i o m e d i c a s U n i v e r s i d a d Nacional, Mexico) described recent progress in understanding the reassortment of the segmented genome and identification of segments coding for the different viral proteins, and their analysis in different areas of the world. Several other dramatic instances of how organisms have avoided elimination in the face of active immunity were d e s c r i b e d . For e x a m p l e in amebiasis (Jesus Calderon, Instituto Politecnico Nacional, Mexico) the trophozoite Enlrmeha hislolytun somehow manages to avoid complementmediated lysis even in the presence of a very active humoral immune response. Calderon described how repeated treatment of a m e b a e with 50% v/v fresh serum results in clones which are m u c h more resistant t h a n are untreated colonies, i.e. an adoptive mechanism has been induced (or selected). Interestingly, inhibition of

(iniUl. jrinr: fi.'t?

non-toxic) markedly increased the susceptibility of the tro]jhozoites. This raises the possibility that in certain instances a combined pharmacologic and immunologic approach may be fruitful. It also serves as an example of where a detailed study of the interaction of the parasite with the host can provide leads for therapeutic intervention. W. F. Piesscns (Harvard University) described t h e ' i m m u n o l o g i c maze' which attends lymphatic filariasis. This ancient parasite can find comfort in almost every verteb r a t e species except mice, which hampers work in the laboratory. T h e [posters, given mainly by members of the Mexican Society of Immunology, covered some projects relating to lymphoid cell and macrophage receptors, lymphokines, immunochemistry and autoimmune p h e n o m e n a , but m a i n l y reflected some h e a l t h p r o b l e m s in M e x i c o (cysticercosis, onchocerciasis, leprosy, tuberculosis and amoebiasis). Recent progress in cysticercosis was discussed by Carlos Larralde (Instituto Investigaciones Biomedicas Unuksidad Nacional, Mexico). T h e r e has been considerable difficulty in diagnosis, but an increased sensitivity of the assay method, in conjunction with the finding that cerebrospinal fluid cont a i n s IgG a n t i b o d i e s to a major antigen B and also to an antigen yet to be defined, should make it possible to detect all cysticercosis cases. It is also novel that a surface antigen of the parasite is fibronectin-like and interacts strongly with collagen a n d v a r i o u s cell t y p e s of t h e b o d y . Whether this interaction diverts the i m m u n e response is not known. Distressingly, there is now solid documentation that in some infections the vigor of the cellular and humoral immune response correlates directly with the severity of clinical pathology. Progress in understanding similar events in streptococcal and mycobacterial diseases were discussed by J o h n Zabriske (Rockefeller University), M . D a n n e n b e r g (Johns H o p kins) and E. Bullock (University of Cincinnati). In all these instances there appears to be a complex tug of war between activating and suppressing factors of the i m m u n e response; in any particular instance the protective efficacy of the ' i m m u n e ' response may depend upon the isotype and specificity of the immunoglobulins procimkl. ml p.59

BCG or Coryni'bacti'rtum parvum infection. Modulation of antigen expression can also be observed m vitro, as the cells p h a g o c y t o s e , a d h e r e or r e s p o n d to l y m p h o k i n e s . A n o t h e r monoclonal recognizes an antigen which is d e t e c t a b l e on a c t i v a t e d mouse m a c r o p h a g e s (and polym o r p h s ) but not on r e s i d e n t or thioglycollate-elicited macrophages. These observations are most reasonably explained not by the existence of different subpopulations of macrophages but by quantitative change in the expression of these particular antigens as macrophages mature or became activated. W h a t is not yet known is whether ail macrophage antigens will behave similarly: wellcharacterised antisera are not yet available in sufficient numbers. Progress will be slowed if, as seems likely, there are i m m u n o d o m i n a n t determinants c o m m o n to all or many of the functionally defined subsets. Nevertheless t h e r e are p l e n t y of macrophage biologists willing to bet that this approach, and other emerging techniques like macrophage hybridoma production and cloning, will soon illuminate the development of macrophage heterogeneity. For the moment, despite exposure on this occasion to the brilliant alpine sunshine of Davos, the answers to some crucial questions remain in shadow. The full proceedings of the meeting will be published later this year in 'Macrophages and NK Cell Regulation and Function' (eds S. Nermann and E. Sorkin) by Plenum Press.

uo/iji'y

11x1(11

Vaccines and infectious disease — i^uUl. ho/ii ji >^])hages

duced, ;is well as the nature o\ the cellular res|>onses. Naturally oecurrint^ changes in the balance of these sometimes lead to 'self-cure\ A />iior/ this gives one hope that mani[)ulations of the immune system by the clinician could lead to similar salutorv results. Indeed, some of the significant regulatory factors in immune responses are becoming understood; for example the immune resjjonse genes and their products, the !a antigens (discussed by Ethan M. Shevach. NIH), which control T-c;e!i and macrophage activation. However, nothing presented at this symposium suggested that such therapeutic hne tuning of immune regulation will be possible in the near future. Similarly, while there is considerable progress in understanding the mechanisms of antil>odv-mcdiated effector functions, the activation and action of complement, macro-

m

and granulocytes {reviewed by Henr\ Metzger (Nil I), Irma (iigli (New \'ork L'niversitv. Celso Bianco Sl.'W Medical Clenter) and John Ciallin (Nlil)), the possibility of manipulating these effector functions, for example pharmacologically, still seems a bit futLiristic, The free discussion at the end of the meeting led by John David (Harvard), touched on the relative contributions towards the eradication of these infectious scourges by basic research into immune mechanism.s on one hand and on the other, research on vaccine development. There was general agreement that, leaving all other issues aside, those working in countries in which these diseases are prevalent need to follow both approaches. Strategy for future w-ork is common to most infective diseases: clarification of effective immunity, be it cell-mediated or antibodv-

meciiated; the isolation of antigens which can induce protective immunity and the search for successful vaccination procedures. However, a concensus on whether the pnricipa/ effort should be to develop vaccines as rapidly as possiljle using currently available technic^ues and knowledge, rather than to develop new knowledge, was more difhcult to achieve. Ihniry Mcizurr i\ Si'd'claryjl reasurcr of ihr Anirriiari Asux ial/(»i nj Iiiuniin()l:')() RncknUf Pikr. Brihrsda. Ml) 2(X)l.f. (\S.A. Hn^iilli' Askuiias is m fhf Division of hni>iuunloi]^y

Vaccines and infectious disease.

Vaccines and infectious disease. - PDF Download Free
274KB Sizes 0 Downloads 7 Views