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need special treatment; but direct challenge with aciddrinks and histamine inhalation is too complex ascreening test for those at risk. The best strategy may beto consider gastro-oesophageal reflux as a possibleexacerbating factor in any child whose asthma or severenocturnal symptoms are unresponsive to medicaltreatment in full dosage.

Help for T cellsTHE principle underlying vaccination-that is,

exposure to a particular antigen in order to elicit aspecific immune response to the same and to relatedantigens-is ancient, widely applied, and almost

universally approved. By contrast, non-specific"pharmacological" stimulation of the immune system,though advocated in various forms for many decades,still has no assured place in orthodox therapy. Manyconsider George Bernard Shaw to have had the lastword on the subject when he lampooned Sir Ralph("Stimulate the phagocytes") Bloomfield-Boningtonin The Doctors Dilemma. Those who take a lessdismissive view can point to a substantial body ofevidence from in-vitro experiments and work in

animals, and even the occasional dramatic clinical

response, to suggest that there is something of realvalue in the idea of non-specific immune stimulation.They would argue that the practical difficulty lies notin identifying immunostimulatory agents or "factors",of which there seem to be a great many, but in matchingone or more of these to the precise needs (deficiencies)of the individual patient.Most modern work on enhancement of immune

function is concerned less with phagocytes than withlymphocytes, and particularly with T cells, which havea pivotal role in the integrated immune response.’ 1Their performance can be measured in vitro in terms ofproliferative response to mitogens, the’ability to lysetarget cells, and the production of soluble lympho-kines, including those that help B cells to increase theoutput of antibody. It is more difficult to quantifychanges in immune function in vivo but increases inthe numbers of circulating lymphocytes and in

immunoglobulin levels, the development of positivetype IV ("delayed") hypersensitivity skin reactions,and, less commonly, evidence of tumour regression,have all been used as tests of the efficacy of immunestimulants.There are two broad classes of agent that consistently

give positive results in at least some of these assays-adjuvants and humoral factors. They are collectively,and inelegantly, known as "biological responsemodifiers".2 Adjuvants may be immunogenic in theirown right, the best-known examples being the waxycell walls of gram-negative bacteria such as Myco-bacterium tuberculosis or BCG, Bordetellapertussis, andCorynebacterium parvum. Mineral oils and certainmineral aggregates such as silica or kaolin also enhance

1. Broder S, Muul L, Waldmann TA Suppressor cells in neoplastic disease. J Natl CancerInst 1978, 61: 9-1 1.

the response to concurrently administered antigen;Freund’s adjuvant, much favoured in immunologicalresearch, is a suspension of M tuberculosis in mineraloil. All these preparations seem to work in several ways.They attract macrophages to the site of injection,thereby enhancing antigen processing and presen-tation, but they also affect the rate of dispersal ofinjected antigen and many have additional direct

stimulatory effects on some classes of lymphocyte.Lymphocyte stimulation seems to be the principalmode of action of a further series of otherwise unrelated

adjuvants including synthetic polynucleotides,vitamin A, and the anthelmintic drug levamisole.1-1Most "biological response modifying" humoral

factors are actually produced by participating lympho-cytes in the course of an immune response and theirexistence has been inferred from both experimentaland clinical observations dating back for many years."Transfer factor", for example, which was in vogue inthe 1960s, was probably a mixture of lymphokines.2,6Interest in these substances is now undergoing a revivalas more and more of them are being purified,sequenced, and even synthesised by molecular cloning.There is, for example, a family of hormones isolatedfrom, or originating in, the thymus and given namessuch as thymosin, thymopoietin, and thymostimulin.Since they are produced by epithelial cells rather thanby lymphocytes, they are not strictly lymphokines buttheir biological role is to induce maturation,differentiation, and proliferation of T cells.

Chemically they are peptides of low molecular weight(below 10 000).’ All the lymphokines analysed to dateare also relatively small peptides. Their system ofnomenclature is still confused since individual factors,defined biologically, have a disconcerting habit ofturning out to be chemically heterogeneous. Neverthe-less, a few are now very well characterised, particularly"interleukin 2" (IL2), the principal component of "Tcell growth factor" .8,9 It is a partly species-specificpeptide of molecular weight 15 000, secreted mainlyby antigen-stimulated or mitogen-stimulated T helpercells, and will sustain the growth and function of allclasses of lymphocyte, provided that these have beenactivated beforehand; in the case of T cells theactivation and induction of IL2 receptors is mediatedby antigen plus interleukin 1 (ILj), a product ofmonbcytes and macrophages. Defects in production of,or response to, It2 have been suggested as the basis forvarious immunological disturbances, and therapeutictrials of purified or biosynthetic IL2 have been

2. Roitt I, Brostoff J, Male D. Immunology Edinburgh: Churchill Livingstone, 198518·5-18·6

3 Weir DM, ed. Handbook of experimental immunology, 3rd ed Oxford: Blackwell,1978.

4 Klein J Immunology the science of self-nonself discrimination New York: JohnWiley, 1982.

5. Woodruff MFA. The interaction of cancer and host: Its therapeutic significance. NewYork Grune and Stratton, 1980.

6 Lawrence HS Transfer factor. Adv Immunol 1969; 11: 195-2667 Trainin N, Pecht M, Handzel ZT. Thymic hormones, inducers and regulators of the

T-cell system. Immunol Today 1983; 4: 16-21.8 Altmann A. T-cell growth factor (interleukin-2). Immunol Today 1981, 2: 1-3.9 Gullber M, Ivarsa F, Coutinho A, Larsson E Regulation of T cell growth factor

production arrest of TCGF production after 18 hours in normal lectin-stimulatedmouse spleen cell cultures. J Immunol 1981, 127: 407-11.

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undertaken in patients with primary or acquiredimmunodeficiency states, including recipients of bonemarrow grafts. Infusion of ILz, in some cases togetherwith "killer" lymphocytes activated in vitro with IL2,has also been tried in a few patients with cancer and,inevitably, in AIDS. Therapy has been limited bytoxicity, notably fever, malaise, thrombocytopenia,fluid retention, and disturbance of liver function, whilethe benefits so far have been inconsistent and

unpredictable. The situation is reminiscent of the earlydays of interferon (IFN) therapy-which is hardlysurprising since interferons - are themselves

lymphokines and the biological effects of IL2 probablydepend to a large extent on interactions with IFN-y andother humoral factors. 10-14Even if abnormally low levels of a specific lympho-

kine, such as IL2, can be demonstrated in a particularclinical setting, it is impossible at present to determinewhether this is cause, effect, or a bit of both. It is,however, unlikely to be an isolated abnormality. Sinceinteraction is the very essence of the immune system, .we should not be surprised at the emerging evidence ofcomplexity in the sphere of lymphokines. We shouldrecognise that it is unrealistic to expect dramatic

therapeutic results at this stage but unwise to discountthe future clinical relevance of this line of research.

EXTRACRANIAL TO INTRACRANIAL BYPASS ANDTHE PREVENTION OF STROKE

IT is difficult to evaluate prophylactic treatments that havemodest, and yet clinically useful, effects on some distantoutcome. This, along with therapeutic optimism on the partof doctors and a desire to have something done on the part ofpatients, has led to the widespread use of unproven and oftenineffective treatments. Worse still, lack of proper evaluationcan lead to abandonment of effective treatments when

something new looks, in theory, more promising. Nowhereare these dilemmas more conspicuous than in the preventionof stroke. All we know for certain is that the risk of stroke canbe reduced by detection and effective treatment of

hypertension, although there is a price to pay in unwantedeffects of drug therapy. There is some evidence that, aftertransient ischaemic attack (TIA) and minor ischaemic stroke,long-term aspirin reduces the risk of stroke and seriouscardiovascular events.2 What the dose of aspirin should be,3and whether it reduces the risk of disabling as well as mildstrokes is uncertain. Dipyridamole is widely prescribed buthas nothing to offer over and above aspirin alone in TIA

10. Grimm EA, Rosenberg SA Production and properties of human IL2. In- Fathman G,Fitch F, eds. Characterisation and utilisation of T lymphocyte clones. New York:Academic Press, 1982. 57-82.

1 1. Gillis S, Mochizuki DY, Conlon PJ, et al Molecular characterisation of interleukin 2Immunol Rev 1982; 63: 167-209.

12 Kolitz JE, Welte K, Sykora K-W, Mertelsmann R Interleukin 2: a review ArzneimittelForsch (Drug Res) 35: 1607-15.

13. Krammer PH, Hamaan U, Hultner L, et al The activity of lymphokines secreted bynormal and malignant T cells. Semin Immunopathol 1984, 7: 291-98

14 Rosenberg SA, Lotze MT, Muul LM, et al Observations on systemic administration ofautologous lymphokine-activated killer T-cells and recombinant interleukin-2 topatients with metastatic cancer. N Engl J Med 1985; 313: 1485-92.

1. Editorial Treatment of hypertension: the 1985 results. Lancet 1985; ii: 645-47.2. Dyken ML Editorial Transient ischemic attacks and aspirin, stroke and death;

negative studies and type II error. Stroke 1983; 14: 2-4.3. Hirsh J Progress review The relationship between dose of aspirin, side-effects and

antithrombotic effectiveness Stroke 1985; 16: 1-4.4 American-Canadian Co-operative Study Group. Persantine aspirin trial in cerebral

ischaemia Part II. endpoint results Stroke 1985, 16: 406-155 Easton JD, Sherman DG Management of cerebral embolism of cardiac origin Stroke

1980, 11: 433-42.6 Warlow CP Carotid endarterectomy does it work? Stroke 1984, 15: 1068-76.

patients;4 anticoagulation is often used in patients with acardiac source of embolism, but the ratio of risk to benefit isvery unclear;5 while carotid endarterectomy has never beenproperly evaluated6 despite the fact that it is now said to be(apart from coronary bypass) the commonest vascular

surgical procedure in the USA, where nearly 100 000 suchoperations are done every year.’ The quickest, most accurate,and most believable method to evaluate suggested treatmentsin this context is the randomised clinical trial with a sufficientnumber of patients to get a reasonable estimate of anybenefit-and we have known this for 20 and more years.8 Forthe prevention of stroke, this methodology has beenembraced by physicians-and is probably why we know somuch about the effect of treating hypertension-but eitherignored or rejected by surgeons. It is therefore to the verygreat credit of the neurosurgeons, who in the past have beenslow to do clinical trials,9 that they have combined withneurologists and statisticians to evaluate properly anotherproposed prophylactic treatment which is already beingcommonly used around the world, the extracranial to

intracranial (EC-IC) bypass.About 10% of patients with carotid-distribution TIA or

mild ischaemic stroke have atheromatous occlusion or

inaccessible stenosis of the symptomatic internal carotidartery (ICA) or middle cerebral artery (MCA).1O They are atparticular risk of ipsilateral ischaemic stroke but, since theyalmost always have widespread atheromatous vascular

disease, they are also liable to have strokes in other territoriesand cardiovascular incidents. These arterial lesions cannot be

operated on directly (carotid endarterectomy beingtechnically possible only if the ICA stenosis is accessible at itsorigin) but they can be bypassed; a branch of the externalcarotid artery (ECA), usually the superficial temporal butsometimes the occipital, is taken through a burr hole andanastomosed to a cortical branch of the MCA on the surface ofthe brain. This surgical collateral may, in theory, improveblood flow distal to the inaccessible or inoperable arteriallesion, protect the brain from ischaemic damage, and perhapsenhance the fragmentation of any emboli that arrive fromproximal thrombi. On the other hand, there is a risk of strokeor even death as a result of the procedure; the bypass couldactually facilitate the passage of emboli from proximal.sitessuch as the ECA origin, aortic arch, or heart; and thedisturbed flow dynamics in the MCA bed may increase thechance of MCA occlusion.

Here, then, is a classic therapeutic dilemma-a technicallyfeasible operation looking for an indication, patients whoseem to need it, theoretical arguments in favour and against,small case-series reported by enthusiasts, and typicallyconservative and doubtful physicians dragging their feet. Weare indeed fortunate that the EC-IC Bypass Study Grouptook up the challenge in 1977, was funded to the tune of ninemillion dollars by NIH to meet it, and has now reported whatmust be a landmark trial in the assessment of any surgicalprocedure and certainly in the surgical prevention of

stroke.II,12 The trial design and discipline were exemplary.

7 Dyken ML, Pokras R. The performance of endarterectomy for disease of theextracranial arteries of the head. Stroke 1984; 15: 948-50.

8. Peto R, Pike MC, Armitage P, et al Design and analysis of randomised clinical trialsprolonged observation of each patient 1 Introduction and design. Br J Cancer1976, 34: 585-612.

9. Haines SJ. Randomized clinical trials in the evaluation of surgical innovation. JNeurosurg 1979, 51: 5-11

10 Warlow CP. Transient ischaemic attacks In Matthews WB, Glaser GH, ed. Recentadvances in clinical neurology 3. Edinburgh: Churchill Livingstone, 1982:191-214

11. The EC/IC Bypass Study Group The international cooperative study of

extracranial/intracranial arterial anastomosis (EC/IC Bypass Study): methodologyand entry characteristics Stroke 1985, 16: 397-406

12. The EC/IC Bypass Study Group Failure of extracranial/intracranial arterial bypass toreduce the risk of ischaemic stroke. Results of an international randomised trial. N

Engl J Med 1985, 313: 1191-200.