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MANY ANIMAL MODELS and ongoing clin-ical trials have used suicide-gene

therapy for the treatment of gliomas inthe brain. A common theme of thesetherapies is the delivery of the herpessimplex virus-1 thymidine kinase (HSV-1-TK) gene through replication-incom-petent adenoviral (Ad) or retroviralvectors to tumor cells. After viral infec-tion, gancyclovir treatment selectivelykills transduced cells and non-specifi-cally damages other cells in close prox-imity, by what is known as the‘bystander effect’1. In this issue ofNature Medicine, Dewey et al. raise im-portant concerns about the long-termeffects of adenoviral-mediated suicide-gene therapy in the brain2.

Dewey et al. studied the effects of ade-noviral-mediated suicide in the rat CNS-1 tumor model, which has been shownto accurately reflect the infiltrativetumor growth observed in humangliomas3. Treatment of CNS-1 tumorswith a single dose of Adv/HSV-1-TK, fol-lowed by gancyclovir, induced chronicinflammation that could still be de-tected at 3 months after therapy.Despite tumor eradication, chronic ac-tive inflammation was demonstrated bythe presence of macrophages and CD8+

T cells at the original tumor site, in ad-dition to microglia and astrocyte activa-tion. There was localized demyelinationin the area of the original tumor. Unlikeprevious studies using adenoviral vec-tors in the brain, Dewey et al. reportthat HSV-1-TK transgene expression isstable, and can be detected for up to 3months after therapy. The distribution

of HSV-1-TK was widespread, and ex-pression was found in both the ispilat-eral and contralateral hemispheres. Toour knowledge this is the first study todocument chronic inflammation afterAdv/HSV-1-TK suicide-gene therapy inthe brain, and raises important issues toconsider in developing strategies fortreatment of brain tumors.

It is important to determine what fac-tors induce the chronic inflammationseen after Adv/HSV-1-TK tumor therapy.There are three potential explanations,each of which have been addressed inthe paper by Dewey et al. The first is thatthe response is directed toward tumorantigen(s) released when CNS-1 cells arekilled and the debris are eliminated bymacrophages. This response would betumor-specific and favorable, as itwould theoretically induce an anamnes-tic response that might prevent tumorrecurrence. The authors demonstratethat this is a reasonable conclusion, asperipheral priming of rats with mito-mycin C-treated CNS-1 cells protectedagainst a lethal intracranial challenge ofCNS-1 cells.

A second possibility is that the chronicinflammation is vector-induced. This re-sponse would not be desirable, as itwould indicate that the immunity wouldnot be tumor-specific. Dewey et al.demonstrate that intracerebral injectionof Adv/HSV1-TK alone leads to the localaccumulation and persistence of CD8+

lymphocytes at the injection site up to 3months after viral inoculation. Thischronic inflammation may be the resultof persistent adenoviral antigen expres-sion, due to the ‘leaky’ nature of first-generation replication-incompetentadenoviral vectors4. Therefore, presenta-tion of these de novo-synthesized viralproteins in the context of major histo-compatibility molecules in the brainmay lead to the generation of anti-viralimmunity manifested as chronic inflam-mation. However Dewey et al. rule outthis possibility by demonstrating thatHSV1-TK expression in the hemispherecontralateral to the tumor does not in-duce chronic inflammation.

Another possibility is thatmacrophages may be infected with re-combinant adenovirus and chronicallystimulate antigen-specific T cells.Indeed, it has been shown thatmacrophages can be infected with re-combinant adenoviral vectors5. Deweyet al. report strong HSV1-TK immunore-activity that overlaps with macrophagedistribution in the ipsilateral hemi-sphere of the brain. However, it is notclear if macrophages participate in theinitiation of the chronic inflammationseen after Adv/HSV1-TK therapy in thismodel system.

A final possibility is shown by experi-ments that demonstrate the synergy be-tween vector and gancyclovirtreatments. A single intracerebral injec-tion of combined Adv/HSV1-TK andgancyclovir led to increased numbers ofCD8+ T cells in the brain 3 months aftertherapy, as compared with what was ob-

Inflammatory thoughts about glioma gene therapyGene therapy for treatment of glioma often involves delivery of herpes simplex virus-1 thymidine kinase gene. A

new study shows that this approach can induce chronic inflammation, and raises important questions about currentadenoviral-based clinical trials (pages 1256–1263).

TAMMY KIELIAN &WILLIAM F. HICKEY

infected cells from spreading their cap-tured prey may be a useful approach toTSE therapy that may also be applicableto other infectious diseases.

1. Prusiner, S.B., Scott, M.R., DeArmond, S.J., & Cohen,F.E. Prion protein biology. Cell 93, 337–348 (1998).

2. Eklund, C.M., Kennedy, R.C., & Hadlow, W.J.Pathogenesis of scrapie infection in the mouse. J.Infect. Dis. 117, 15–22 (1967).

3. Fraser, H. & Dickinson, A.G. Pathogenesis of scrapiein the mouse: the role of spleen. Nature 226,462–463 (1970).

4. Kimberlin, R.H., & Walker, C.A. Pathogenesis ofmouse scrapie: dynamics of agent replication inspleen, spinal cord and brain after infection by differ-

ent route J. Comp. Path. 89, 551–562 (1979).5. Kuroda, Y., Gibbs, C.J. Jr., Amyx, H.L. & Cajdusek,

D.C. Creutzfeldt-Jakob disease in mice: persistentviremia and preferential replication of virus in low-density lymphocytes. Infect. Immunol. 41, 154–161(1983).

6. Klein, M.A. et al. A crucial role for B cells in neuroin-vasive scrapie. Nature 390, 687–690 (1997).

7. Klein. M. A. et al. PrP expression in B lymphocyte isnot required for prion neruoinvasion. Nat. Med. 4,1429–1433 (1998).

8. Raeber, A. J. et al. PrP-dependent association of pri-ons with spleenic but not circulating lymphocytes ofscrapie-infected mice. EMBO J. 18, 2702–2706(1999).

9. Brown, K. L. et al. TSE replication in lymphoid tissuesdepends on PrP expressing follicular dendritic cells.Nat. Med. 5, 1308–1312 (1999).

10. Van Keulen, L.J., Schreuder, B.E., Vromans, M.E.,Langeveld, J.P. & Smits M.A. Scrapie-associatedprion protein in the gastrointestinal tract of sheepwith natural scrapie. J. Comp. Pathol. 121, 55–63(1999).

Division of Neuropathology

Institute of Pathology

Case Western Reserve University

School of Medicine

10900 Euclid Ave.

Cleveland OH 44106-4943

Email: mxs92@po.cwru.edu or

Email: pxg13@po.cwru.edu

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1238 NATURE MEDICINE • VOLUME 5 • NUMBER 11 • NOVEMBER 1999

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served after Adv/HSV1-TK treatmentalone. This finding indicates that thechronic inflammation may be mediatedby damage induced by the ‘bystander ef-fect’ in concert with immunity directedagainst adenoviral proteins.

One of the most intriguing findingsof Dewey et al. is that localized demyeli-nation was found in the area where thetumor had originally resided. There areseveral mechanisms by which this de-myelination may have occurred. First,peritumoral edema induced duringtumor expansion could have compactedsurrounding normal tissue, leading tooligodendrocyte death and localized de-myelination. Alternatively, products re-leased by activated macrophages (suchas nitric oxide or superoxide) and/orCD8+ T cells (such as perforin orgranzyme B) may lead to the nonspe-cific destruction of oligiodendrocytesand/or myelin. It is unlikely that the ob-served demyelination is autoimmune-mediated, as the area of demyelinationwas restricted to the original tumor bed,whereas autoimmune demyelinationmight be expected to be present with a

much wider distribution. Yet this im-portant possibility cannot be ignored.The presence of an immunospecific in-flammatory reaction against tumor anti-gens could conceivably lead to thegeneration of a response against unin-tended native antigens through the pu-tative mechanism of epitopespreading6,7. Such a mechanism wouldrepresent a considerable ‘downside’ tosuicide gene therapy may exist.

This study raises important points re-garding current adenoviral-based clini-cal trials for human gliomas. Thereshould be concern about the potentialof this technique to induce chronic ac-tive inflammation which may ulti-mately have negative consequences onthe functional integrity of the brainparenchyma. It will be important to de-termine whether these findings extendfrom the animal model to human braintumors. Further study to identify theantigenic stimulus of this chronic in-flammation is warranted to ascertainwhether it will interfere with the ad-ministration of additional vector or theinduction of a secondary immune re-

sponse upon tumor recurrence.

1. Freeman, S.M., Ramesh, R. & Marrogi, A.J. Immunesystem in suicide-gene therapy. Lancet 349, 2–3(1997).

2. Dewey, R.A. et al. Chronic brain inflammation andpersistent herpes simplex virus 1 thymidine kinaseexpression in survivors of syngeneic glioma treatedby adenovirus-mediated gene therapy: Implicationsfor clinical trials. Nature Med. 5, 1256–1263 (1999).

3. Kruse, C.A. et al. A rat glioma model, CNS-1, withinvasive characteristics similar to those of humangliomas: A comparison to 9L gliosarcoma. J. Neuro-Oncol. 22, 191–200 (1994).

4. Yang, Y. et al. Cellular immunity to viral antigenslimits E1-deleted adenoviruses for gene therapy.Proc Natl. Acad. Sci. USA 91, 4407–4411 (1994).

5. Worgall, S. et al. Selective expansion of alveolarmacrophages in vivo by adenovirus-mediated trans-fer of the murine granulocyte-macrophage colony-stimulating factor cDNA. Blood 93, 655–666 (1999).

6. McRae, B.L., Vanderlugt, C.L., Dal Canto, M.C., &Miller, S.D. Functional evidence for epitope spread-ing in the relapsing pathology of experimental au-toimmune encephalomyelitis. J. Exp. Med. 182,75–85 (1995).

7. Miller, S.D. et al. Evolution of the T-cell repertoireduring the course of experimental immune-medi-ated demyelinating diseases. Immunol. Rev. 144,225–244 (1995).

Department of Pathology

Dartmouth Medical School

Dartmouth Hitchcock Medical Center,

Lebanon, New Hampshire 03756, USA

One of the oldest puzzles in vision re-search involves the mechanisms bywhich the context of a stimulus caninfluence the perception of its rela-tive brightness. For example, thetwo surfaces of the object shownhere are physically identical (of equalluminance), but appear to be differ-ent, because of opposing light anddark luminance gradients along astep boundary. These different lumi-nance gradients make the uppersquare appear darker than the lowersquare. Vision researchers have longthought that this phenomenon,known as the ‘Cornsweet effect’,could be explained by the receptivefield properties of retinal ganglioncells.

Dale Purves and colleagues havere-examined this hypothesis, and inthe 1 October issue of The Journal ofNeuroscience, they propose that per-ceptions of luminance are not deter-mined by retinal physiology, but byempirical associations made in the cir-cuitry of the visual cortex. Investigationof different factors that enhance or re-

duce the Cornsweet effect suggest thatthe brain accumulates information from

past visual stimuli and applies it to thestimulus confronting the observer at anygiven moment. Thus, the various pieces

of information included in this image,such as the luminance gradient, perspec-

tive, orientation, texture and back-ground, all indicate to the viewer,based on past visual experience, thatthe two areas are likely to differ inbrightness. Accordingly, this is theperception experienced.

The authors of the paper believethat this empirical strategy of visualprocessing has been selected forthroughout evolution. “Since all vi-sual stimuli are ambiguous, the mostefficient way for an animal to re-spond is to generate an associationbased on what the stimulus has usu-ally turned out to be, and then actupon that,” explained Purves. “Theanimal that couldn’t do this effec-tively probably got eaten by a saber-toothed tiger.”

Purves and colleagues are also in-vestigating this empirical theory interms of other visual qualities that af-fect luminance perception, such as

color (reported in the November issue ofNature Neuroscience).

KRISTINE NOVAK

Shedding new light on luminance perception

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