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seems implicitly to accept that the brain monitors the effects ofcyclophosphamide but rejects the possibility that relatively specific information about those effects may reach the brain. The extent of such afferent input is an empirical question which can be approached by any number of experimental strategies. One of these is conditioning. It was, after all, the demonstration of a conditioned taste aversion that enabled Dwyer to infer that the conditioned animals experienced 'nausea ' (technically, of course, we need not infer any conscious experience to ex- plain conditioning). We have shown that conditioning procedures can establish not only a taste aversion, but also im- munosuppression, a finding entirely con- sonant with a voluminous literature on conditioned physiological and pharma- cological responses 5. The brain 's afferent input (and efferent output) must be com- mensurate with that ability. Just how specific that input (and output) will prove to be remains to be determined, but

experiments which condition the uncon- ditioned response to antigen suggest fairly specific abilities.

Again, the physiological mechanisms which underlie these effects have yet to be uncovered m which, of course, has no bearing on the phenomenon itself. The innervation of lymphoid organs repre- sents just one of a growing number of potential pathways that link the CNS with the immune system. Although we cannot do justice here to the evidence of both afferent and efferent pathways, one point should be noted in passing. The authors of the papers we cited have addressed the possibility that innervation of lymphoid organs serves only to control blood flow (which, incidentally, might well have profound effects on lymphocyte traffic); their results, however, strongly challenge this assumption. Many of the nerve fibers appear to have no association with the vascular supply; some appear to terminate on mast cells; and denervation has potent effects on immune responses.

We recognize the difficulties that data such as ours may introduce for some traditional orientations but, to para- phrase Dwyer's conclusion, lack of atten- tion to the relevance of controls and a failure to consider the available literature can, unfortunately, obfuscate rather than clarify, thereby aborting meaningful progress in this new area.

DANA BOVBJERG NICHOLAS COHEN

ROBERT ADER

The Center for Brain Research and Departments of Microbiology (Division of Immunology) and Psychiat~7 , University of Rochester School of Medicine and Dentistry, Rochester, N Y 14642, USA.

References 1 Schwartz, B. (1978) Psycholog~ of Learning and

Behavior, Norton, New York 2 Spiker, V. A. (1977) PsychoL Rec. 27, 753 3 Logue, A. W. (1979) PsychoL Bull. 86, 276 4 Domjan, M. (1980)Adv. Study B 11,275 5 Eikelboom, R. and Stewart, J. (1982) Psychol.

Rev. 89, 507

DNA strand breaks and differentiation SIR,

We would like to clarify a point made by Alan Johnstone and Gwyn Williams in their article about DNA strand breaks and differentiation (Immunol. Today, 1983,January, 4, 8-9). They referred to our paper on the mechanism of inhibition by UV-irradiation of the mitogenic activ- ation ofl'ymphocytes 1 . They suggest that if we had known about the DNA strand breaks in resting peripheral blood lym- phocytes, we would have been 'less puzzled'. This misrepresents the point of our paper, which is germane to this topic.

We examined the effects of prior UV- irradiation on a number of parameters of the activation of human blood lympho- cytes by concanavalin A (Con A). We looked in particular at the effects of U V on the activation by Con A of the (Na, K)- ATPase and cation fluxes associated with this activation. This aspect of lymphocyte mitogenesis is early (detectable within 5 minutes of mitogen addition), essential for all subsequent events of cell activation (although this has not yet been shown for DNA strand-break repair) and, most important, is independent of DNA trans- cription and replication, and protein synthesis 2,3 .

We found that within two hours of the irradiation of human blood lymphocytes with U V (we did not look any earlier), the activation of membrane transport which normally results from mitogenic activ- ation had been prevented. We concluded that the primary inhibitory effect of UV was at the level of the membrane. This inhibition was therefore independent of any effect of U V on DNA (see above). This conclusion would not have been altered by knowledge of DNA breaks. We clearly acknowledged in our paper that damage to DNA must have been caused by UV-irradiation. Our point was that this did not matter, since UV inhibited another system whose activa- tion is also essential for mitogenesis, and this activation is independent of the nucleus. Therefore, whether or not U V causes strand breaks or inhibits their repair, it should inhibit mitogenesis anyway through its inhibition of the (Na,K)-ATPase and membrane trans- port. In this regard it is noteworthy that the purine and pyrimidine analogs which Greer et al. ~ have shown to cause DNA strand breaks in and inhibit mitogenesis of mouse lymphocytes have no effect on membrane transport oron other events of lymphocyte activation.

We do not know the mechanism of the inhibition by UV of(Na,K)-ATPase act-

ivation. It seems improbable that DNA strand-break repair could regulate an increased rate of ion transport; one could more easily envisage a dependence of DNA repair on (Na,K)-ATPase activa- tion, given the pleiotropic effects of this enzyme 2,3.

Clearly, both DNA strand-break repair and activation of membrane transport are essential and early events in lymphocyte activation. What is not dear, and needs resolving, is whether and how they are related mechanistically.

TREVOR OWENS ICRF Tumour Immunology Unit, Department of Zoology, University College London, London WCIE 6BT, UK.

J. GORDIN KAPLAN Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.

References 1 Castellanos, G., Owens, T., Rudd, C.,

Bladon, T., Settertield, G. and Kaplan, J. G. (1982) Can.J. Biochem. 60, 854 860 Kaplan, J. G. (1978)Annu. Rev. Physiol. 40, 19-41 Kaplan, J. G. and Owens, T. (1980)Ann. NY Acad. Sci. 339, 191-200 Greet, W. L., Boumah, C. E., Scruple, K. M. and Kaplan, J. G. (1982) Immunobiology 163 (2 4), 179