The Immunobiology of Low-Dose Total-Body Irradiation: More Questions Than Answers Author(s): Akmal Safwat Reviewed work(s): Source:

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RESEARCH RADIATION 153, 599-604 (2000) 0033-7587/00 $5.00 Research Society. ? 2000 byRadiation reserved. in of All rights reproductionanyform

COMMENTARY Irradiation: Questions More ofLow-Dose The Immunobiology Total-Body thanAnswers

Akmal Safwata,b,l
National Cancer Institute, Fom El-khalig,Cairo, Egypt;and b Groupfor Biostatistics Oncology, in Department, aRadiotherapy Northwood, Middlesex,HA6 2JR,UnitedKingdom Gray LaboratoryCancer Research Trust,

IrofLow-Dose A. Safwat, TheImmunobiology Total-Body Radiat. Res. 153, thanAnswers. MoreQuestions radiation: 599-604 (2000). and ment chronic of leukemia low-grade nonlymphocytic
The is Hodgkin'slymphoma. usual practice to giveverylow a totaldose of 1.5 to 2 Gy. Despitethislow dose,low-dose in TBI can inducelong-term remissions the majority paof tients. Immune rather thandirect radiation cell enhancement, is mechanisms which low-dose by killing, one ofthesuggested TBI can exertits effect. Data from animalexperiments have irradiation Low-dosetotal-body (TBI) is used in thetreat-

times week, a to fractions to 0.25Gy)several individual (0.1

TBI shown low-dose could that enhance immune the response the reactive of (1) through augmenting proliferative response theT cellsto mitogenic re(2) stimulation; altering cytokine
the of lease,particularly activation interferon and 112proy of the on duction;(3) increasing expression 112receptors the

in T-cellsurface; facilitating transductionT lym(4) signal

content and (5) phocytes; increasing spleniccatecholamine the a level;and (6) eliminating lowering serumcorticosterone radiosensitive subsetof the suppressor cells. T particularly Data forhumans, thatat leastsomeof scarce,suggest though these mechanisms occurin patients treated with TBI. low-dose Whether theseimmunomodulatory effects responsible are for

theclinical is outcome notyetclear.Muchis still unknown

abouttheimmunobiology low-dose of TBI, itsclinical poten-

hensive the and widespread use knowledge hampers optimal ofthisintriguing potentially and useful treatment in modality clinicalpractice. ? 2000 by Radiation ResearchSociety

and possible with tial, the synergism chemotherapy, biological or This modifiers,immunotherapy. lackofcompreresponse

a a dose times weekuntil cumulative of apgivenseveral thisvery low 1.5 to 2 Gy is reached. proximately Despite in relow-dose is successful inducing TBI dose, long-term as missions hasbeenshown be as effective thecheand to to it (4). motherapy which has beencompared Controlling a malignant defies with suchlowdosesofradiation process that theconventional wisdom "more[dose]is better". is It counterintuitivehard understand. of and to One admittedly thetheories forward explain efficacy low-dose to the of put TBI is that couldbe partly it to attributed a radiation-inducedimmune enhancement than direct rather to of killing tumor byradiation. is basedon someexperimencells This talstudies haveshown that various efimmune-stimulatory fects low-dose of TBI. Basedonthese clinical trials results, of withAIDS usinglow-doseTBI in treatment patients weresuggested 6). Despitegrowing interest thesubin (5, of oflow-dose TBI ject,ourknowledge theimmunobiology is notwelldeveloped is rather and fragmented. Thiscommentary at providing overview the aims an of effects TBI and theposimmunomodulatory of low-dose siblefuture directions laboratory-based clinical for and research. the low-dose Understanding mechanisms which by TBI enhances immune the on system havean impact may thedesign protocols use low-dose of that TBI in thetreatment non-Hodgkin's of and lymphoma other malignancies. DATAFROMANIMAL EXPERIMENTS TheAntitumor (Immune-Mediated) ofLow-Dose Effects TBI

The antitumor effects low-dose of TBI areusually studied in animal in models which tumor areimplanted cells in INTRODUCTION thelimbsof various rodents. Effects low-dose of TBI on and of are Low-dosetotal-body irradiation growth suppression metastasis compared (TBI) is a validoption tumor tothose animals in localized irradiation thesame with in thetreatment chronic of leukemia given (CLL) lymphocytic dose. (1) andlow-grade (2, non-Hodgkin's lymphoma 3). A typet that TBI ical treatment schedule of consists 0.1-to0.25-Gy fractions Sakamoto al. haveshown 0.1 Gyoflow-dose to tumor can given mice6 to 15 h before implantation lead SAddress correspondence the authorat the Gray Laboratory. to to a statistically increase thenumber cells in of significant
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of cells. This suppressor inducedproliferation T-helper in incidence 50% ofthemice(TDso)(7). for required tumor be Hashimoto shown has that of could,at leastin theory, triggered the by hepatoma mechanism growth implanted of cells(16). was suppressed 7 days vastarray antigens tumor lines(KDH-8) in rats cell for by produced tumor Immune enhancement TBI andthat could thusbe inducedby two metasafter Gy oflow-dose 0.2 spontaneous a elimination theT-suppressor nodeswas also significantlymechanisms:differential of tasisto thelungsand lymph of and of reduced Localizedirradiation thesamedose (0.2 subset lymphocytes an augmentationtheimmune (8). using direct and/or indirect stimulation T of to the implanted tumor site neither tumor response delayed through Gy) To distant metastasis. excludethat lymphocytes. norsuppressed growth in of was thesuppression metastases due to changes cell Subset Lymphocytes recaused by radiation-induced of of inflammatory 1. Elimination theT-Suppressor trafficking the wereirradiated while action thelungs, animals in their Forlow-dose tospecifically TBI eliminate suppressor the leadblocks. suppression The wereshielded 5-cm with lungs subset lymphocytes, of a certain differential radiosensitivity of lungmetastasis low-dose TBI was thesameas that by shouldexistbetween T-helper the T-suppressor the and The concluded "lowthat in thenonshielded group. author cells. aboutanti-tumour effects dose TBI brought host through One oftheearliest about immune-stimulatory the reports unlike thoseproduced highdose irimmune response, by effects low-dose of irradiation ofan enhanced was primary In it radiation". a later publication thesamegroup, was by if after antibody response 0.05 to 0.25 Gy is administered to in shownthat, contrast localizedirradiation, low-dose immunization. authors The that was due this hypothesized TBI of 0.2 Gy led to a significant increase thetumor in to theelimination a radiosensitive of of subpopulation sup(P tissue-infiltrating lymphocytes < 0.01) (9). T was however, done pressor cells (17). Thisearlystudy, In a study Hosoi and Sakamoto, by low-immunogenicwithout use of the to the techniques characterize modem murine cell carcinoma cells wereinjected into different squamous of A subtypes lymphocytes.later study Spellby the albinomicethrough tailvein.Total-body irradiation of manandAnderson shown a subset cytotoxic has that of T 0.15 to 0.2 Gy, givenfrom h before 3 h after 9 to the that with 0.10 to 0.25 lymphocytes can be killedin vitro of in net cells,resulted a significant supinjection, tumor of radiation exists. Theseradiosensitive are Lytcells oflungcolony formation. results wereob- Gy Similar pression 1,2 lymphocytes (18). served thespontaneous tumor in metastasis model (10, lung et a differential radiosensitivFourquet al. demonstrated 11). between B and T subsets lymphocytes. the of ity They found low-dose that TBI decreased relative the number of PossibleMechanisms Immune Enhancement Lowof by B cellswhile therelative number functioning of increasing Dose TBI T andNK cellsin thespleens irradiated (19). of mice theauthors notexamine various did the Unfortunately, Tumors induce can immune and responses, itis nowacsubsets T cells. So, whileevidence of thata differential mechanisms significant. are ceptedthatinnateimmune exists the and T-suppressor sensitivity between T-helper the which often infiltrate a tumor mass,can deMacrophages, the is refutable. tumor cellsin tissue culture whenactivated a va- cellsis notstrong, idea itself nottotally stroy by of that interferon Also,resting riety factors include y(Infg). 2. Augmenting Immune Parameters Response natural killer for (NK) cellsarespontaneously cytolytic certaintumor Interleukin-2 NK targets. It seemsplausible (I12)-activated cells nowthat low-dose TBI can enhance a (12). the immune display wider lethality in experimental animalsand can response Insofar acquired as is the in immunityconcerned, antitumor cause measurable changes someimmunological parameffects thought be mediated are to thecytotoxic eters T Liu that through (20). Forexample, etal. showed theimmune cells (13). Activation cytotoxic starts of cells with ac- enhancement the causedbylow-dose was associated TBI with tivation and proliferation T-helper of cells, a processthatis an increased catecholamine content lowering and of splenic on critically dependent thepresenceof 112and thesynthesis theserum corticosterone (21). Through presence level the of 112receptors will (14). Interleukin-2 encouragethe deofhormone on effects cells, receptors immunological both of velopment TH1 cells, which is more suitablefor anti- couldlead to an enhanced immune Mostof the response. tumor effects thanthedevelopment TH2 cells. Activated studies theliterature, of in resorted showing to either however, cells will stimulate of T T-helper precursors cytotoxic cells thealteration thecytokine in releaseor theenhanced proto proliferateand differentiate into cytotoxic T cells liferative of the activity lymphocytes (particularly T cells) of secretion cytokines characteristic cell-medi- to mitogenic of through stimuli. ated immunity, namely 112,116,Infg and tumornecrosis Mice infected thepolycythemia-inducing of with strain factor[ (Tnfb) (15). theFriend viruscomplex abnormal (FVC-P) demonstrate The transforming factor3 (Tgfb) secreted the cell regulatory effects similar those to seenwith cellsfrom growth by cells (and indeed some tumor withleukemia. Infected micealso showed loss a cells) can sup- patients T-suppressor of cells through The natural presstheactivation cytotoxic killeractivity these in blocking 112- of Trp53expression.

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micewas decreased their and bonemarrow cells manifest that low-dose TBI increased of secretion 112andInfg(22) a decreased to phytohemagglutinin well as increased as of 112receptors b proliferative response expression (I12ra, and concanavalin (Con A). If untreated, A these andg) on theT-cellsurface Theincreased (PHA) (24). expression micedie within daysof FVC-P infection, they 40 but are of 112 in as receptors activated thymocytes appeared early cured with detectable no virus with and survival as 24 h after low-dose coincided with inthe TBI, which long-term with TBI secretion 112 splenocytes. theother of by On (>370 days)iftreated low-dose (1.5 Gy)on days creased hand, 5 and 12 after administration FVC-P Treatment ofthe with theincreased secretion Infgwas apparent daysafter of 8 low-dose was associated restorationthe TBI with of cellular low-dose andcontinued increase to21 dayspostTBI to up In to immunity.response PHA andConA stimulation, (24). lym- irradiation from mice produce more112 mostofthedatain theliterature to spleensof treated phocytes Though points theT andupto 15times more cellsfrom than untreated mice cells as beingdirectly activated low-doseTBI, some Infg by infected withFVC-P (5, 22, 23). The studies have also data suggest thatindirect activation cells mayalso be T shownrestoration Trp53expression infected of in mice triggered low-dose irradiation. Galdiero al. (28) studet by treated low-dose with ied theeffects radiation alteration thereleaseof of on of TBI (6). In an elegant Hashimoto al. showed et and the that, cytokines monocytes lymphocytes. experiment, by Though auin splenocytes tumor-bearing given Gylow-dose thors of rats 0.2 were interested the in immune that suppression occurs of mRNAexpression thegenesthat encodeInfg and after radiation didnotice greater a release TBI, doses,they high of while that Tgfb decreased. There no ofIll from A-stimulated was Con after radiation low Tnfaincreased, monocytes of all enhancesthe responseof T cells 116 expression mRNAof the114, and1110 genes, of doses. Interleukin-1 which havetheundesirable effect selectively of dif- through the of receptors theT on driving increasing expression 112 ferentiationTH2 cells andinhibiting cell differen- lymphocytes 15). of (14, TH1 tiation. Localizedirradiation thetumor-bearing had of site Ibukiand Goto have reported low-dose that TBI with no effect cytokine on release splenocytes. because 0.02 Gyenhanced Con A-induced the of Also, by proliferationspleof theexpression themRNAthat encodes these that of However, also observed theresponse geneswas nocytes. they notaltered whentumor cells wereirradiated vitro, in the nonirradiated cultured peritoneal with spleno-lymphocytes authors that encode macrophages with suggest themRNAforthegenesthat preirradiated 0.02 and 0.04 Gy were these was to from normal cells about120and145%ofthecontrol, cytokines likely be derived (29). respectively These in thehostanimal results to them theenhancement Con Athat in (9). suggested Liu et al. have shown that low-dose TBI increased the induced ofsplenocytes low-dose irradiation proliferation by of splenic and thymic was notcausedby direct activation splenocytes by of but proliferative reactivity lymphocytes to suboptimal concentrationsvarious of in mice activation macrophages thespleen, that lymof in and the mitogens has also shown that TBI low-dose wereactivated This enhance(21). The same group phocytes indirectly. indirect could stimulate theseeffects facilitation signal ment splenocytes low-dose-irradiated of of macthrough by peritoneal in transductionlymphocytes was observed whenmacrophages collected were (24). rophages In a seriesof studies, irradiation was absent but when macrophages the Nogamiet al. havedemonstrated 4 h after an augmented to stimulation werecollected or 12 h after irradiation It is imporproliferative activity mitogenic (29). 1 of thesplenocytes miceexposed low-dose of to TBI (0.04 tantto remember direct indirect that and activation T of 2 exclusive that and both mechanisms Gy per exposure per day, 5 consecutive days/week, cellsarenotmutually to weeks).These splenocytes responded T-cellbutnotB- maycoexist. cell mitogens further their levels of heatby increasing shock 70 protein (Hsp70)mRNAandHsp72andbymount- TheRadiobiology Immune Enhancement Induced of by The authors also Low-DoseTBI ing a heightened proliferative response. isolatedT cells from spleensof low-dose-irradiated the The question threshold fortheimmune-enhancof dose mice.Theythendemonstrated thesecells possessed that of irradiationa critical Immuneis one. elevatedlevels of Hsp70 mRNA and Hsp72. Theyalso ingeffect low-dose effects weredetected dosesas low as 0.02 with showed these that cellsresponded T-cell to enhancing receptor-specific there someevidence theliterature is in anti-CD3 stimulation producing Hsp70mRNA that more and Gy. Though by more than where higher a Hsp72 and by proliferating extensively T cells there maybe a dose-response relationship of sham-irradiated Hence theauthors mice. stated that T was at dose (29), what actuis response detected a higher cellsandnotB cellsareresponsive low-dose to irradiation allymoreevident a reversal theimmune-stimulatory is of evidence from factthat effect higher the with radiation doses.Forexample, (25, 26). Theydrewfurther stimulation from T to dose splenocytes thymectomized miceanduntreated ofsplenic cellswas seenin miceexposed a daily young old micepossessing involuted an werebothunre- of 0.1 Gy of TBI to a totaldose of 0.8 Gy butnotto a thymus to effect of dose of 2 Gy. In another the sponsive theproliferation-augmenting low-dose cumulative study, reactivity irradiation of mousethymocytes Ill was increased (27). to between 0.025 studies haveexamined cells have shown to 0.1 Gybutwas depressed that T Indeed, when doses(upto0.25 higher

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FIG. 1. The dose-response of cell relationship the plaque-forming and test(LPS) (PFC) assay, y level, lipopolysaccharide assay, interferon ed in spleencells of miceexposedto low-dose irradiation. total-body Data points marked stars significantly with are different < 0.05) from (P sham-irradiated controls. dataaretaken The from tablein a published a by study Liu et al. (24).

Con Gy) weregiven(30). Similarly, A-induced proliferationof spleno-lymphocytes enhanced 0.02 Gy irwas by radiation inhibited 0.2 Gy. This was confirmed but in by in rats, another the where Con A-induced study response was significantly (P < 0.02) after GyTBI than 0.05 higher in sham-irradiated controls. After TBI withdoses higher than0.25 Gy (31), theCon A-induced of response splewas reduced. exampleof thisdose-response An nocytes for in relationship someimmune response parameters mice is illustrated Fig. 1. in All thesedataindicate enhancement theimmune that of occurred and parameters response onlyin a certain very narrow dose range. Thisdose range probably is dependent on theend point tested. The dependence other on factors suchas animal is speciesor thedose rateofradiation still an openquestion. Someoftheimmune enhancement antitumor and effects induced low-dose TBI aretemporary short-lived and by (a fewhours) 23, 29), whileothers, as theincreased such (10, secretion Infg lymphocytes, beenshown last of have to by to 3 weeksafter irradiation Becausemostof the (24). up studiesin the literature werenot designed study to the of immune enhancement intime-response relationship ducedby low-dose tested points end at TBI, they usually one time. Thismakesanyattempt addressing at this only rather One that aspect speculative. canonlysuggest various seem to possessdifferent scales forretime parameters to irradiation. sponses low-dose
DATA FOR HUMANS

Thereareampleclinical datain theliterature attest that to theefficacy low-dose of of TBI in treatment low-grade and (32-35). In an important unparalleled clinlymphomas

ical study Yonkosky al., ninenon-Hodgkin's et by lymphoma patients whomprevious for had chemotherapy failed weretreated withfractionated low-doseTBI (1.2 to 1.8 and scheduled to, Gy).Prior during after therapy, peripheral bloodsamples weretaken enumerate to bloodB peripheral cells usingtheEAC (sheeperythrocytes coatedwith antiandcomplement) E (sheep and body erythrocytes) rosetting cell assays,and to measure proliferative the to responses Con A, PHA and pokeweed The study showed mitogens. a consistent decrease thenumber B cells after in of the of TBI that rose steadily normal to completion low-dose levels within to 8 weeksafter 3 irradiation whether the to or also patient responded therapy not.The study showed that fractionated low-dose TBI appeared enhance to rather thansuppress in vitro the immune in response several patients. The altered numbers percentages B and T and of cells in peripheral blood werecorrelated neither with the clinical nor the outcome. However, findings with treatment were127 to 319% of theinitial values mitogen responses forall fivepatients withcomplete contrast, response. By werenotimproved thepatients in with mitogen responses or progressive disease.Thusclinical unchanged improvement correlated theappearance increase mitogenwith or of induced but in proliferative responses notwith changes the of B-cellpopulations thisstudy (36). Though percentages did notprovethattheseimmune-enhancing were effects for clinical the outcome does (sincecorrelation responsible not necessary meancausation), was veryimportant it in that deTBI couldcausea certain demonstrating low-dose enhancement humans. in greeofimmune Another has the blood lymstudy analyzed peripheral in with or phocytes patients non-Hodgkin's lymphoma advancedcancer whoreceived low-dose TBI. The results indicated thattheproportion thehelper lymphocytes, of T T and T helper-inducerlymphocytes, cytotoxic lymphoincreased low-dose TBI. On theother hand, cytes during the proportion suppressor-inducer of T lymphocytes and T lymphocytes to decreaseslightly suppressor appeared in to of et (37). However, contrast theresults Yonkosky al., thisstudy notattempt correlate observed did to the effects with clinical outcome. any Another looked thedifferential at of group sensitivitythe various subsets after what considered lowlymphocyte they doseTBI. Theystudied patients 30 treated TBI before with bone marrow and transplantation showedthatall major subsetssharing helper the lymphocyte (naive phenotype andmemory) thecytotoxic and to phenotype appeared exhibit invivo in equalradiosensitivity (38). Thedosestested that were of however, in therange 2 to4 Gy,which study, is higher than conventional the definition low dosesof of TBI. Thisis a crucial sinceanydifferential radiosenpoint, between various the of subsets lymphocytes could sitivity havebeenlostat thisdose. Studiesof the immune of system A-bombsurvivors showed someeffect failed find but to conclusive evidence of immune enhancement (39).

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the dataseemto suggest of and of but certain Thus,in humans, available regression suppression medegree tumor in no way provethepresence immune-stimulatory tastases. of the that antitumor is efeffect However, evidence this fects low-dose of attribute causedbytheimmune stimulation remains circumTBI, andwe cannot confidently largely TBI theclinical effects low-dose toimmune of stimulation. stantial. UNANSWERED QUESTIONSANDFUTURE DIRECTIONS
Received: 26, 28, August 1999;accepted: January 2000

REFERENCES aboutimmune enhancement Manyof thequestions by 1. J.A. del Regato, Totalbodyirradiation thetreatment chronic in of TBI remain and further low-dose unanswered require exleukemia.Am. J. Roentgenol.120, 504-520 (1974). lymphogenous studies. example, wouldbe important For it to perimental 2. H. J.Dobbs,A. Barrett, Y. Rostom A. and M. J.Peckham, Total in Br. determine thethreshold is fortheseeffects what dose and bodyirradiation advanced non-Hodgkin's lymphoma. J. Radiol.54, 878-881(1981). it at what dose they lost.Similarly, is notknown are when 3. P. M. Richaud, Soubeyran, Eghbali, Cacon,G. Marit, P. H. B. A. theseimmune how start, longthey last,andwhen changes Broustet R. T. Hoppe,Place of low-dose and total bodyirradiation reacha peak. they in thetreatmentlocalized of follicular NHL: results a pilotstudy. of A comprehensive of immune view stimulation lowInt.J.Radiat.Oncol.Biol.Phys. 387-390(1998). 40, by 4. P. Jacobs H. S. King,A randomised and dose TBI depends ourperception thechainof (imon of of prospective comparison to as treatment the for chemotherapy totalbodyirradiation initial events thatoccurafter low-dose TBI. It is munological) diseases. indolent (1987). lymphoproliferative Blood69, 1642-1646 therefore to what and important investigate other cytokines 5. R. N. Shen, Lu, H. E. KaiserandH. E. Broxmeyer, L. Murine AIDS cells (e.g. monocytes, natural killer in cells) are involved cured lowdosagetotal Adv. by bodyirradiation. Exp.Med.Biol.407, 451-458 (1997). the immunomodulatory effects low-doseTBI. Also, of 6. R. N. Shen,H. E. Kaiserand H. E. Broxmeyer, Curative effect of whether differential a existsbetween the radiosensitivity low dosagetotal-body irradiation murine on AIDS induced split by and subsets lymphocyteslow doses of at suppressor helper Friend virus:theresults thepossible and mechanism. Vivo10, In is stillan open question. Most of theexperimental work 191-199(1996). was doneusinga singlefraction low-dose of TBI in the 7. K. Sakamoto, Miyamoto N. Watabe, effect low-dose M. and The of total on control. To Kagaku Gan of low-dose TBI 14, bodyirradiation tumour Ryoho however, range 0.2 to 0.25 Gy.Clinically, 1545-1549 (1987). [inJapanese] is givenon a fractionated schedule. effect fractionThe of Effects low-dose of total (TBI) on bodyirradiation ationon theimmunomodulatory has notbeenthor- 8. S. Hashimoto, effects rats. tumor-bearing Nippon Igaku Hoshasen Gakkai Zasshi 57, 418Relevant theclinicalsituation to are oughly investigated. 424 (1997). [inJapanese] thequestions abouttheinfluence combining of low-dose 9. S. Hashimoto, Shirato, Hosokawa, Nishioka, Kuramitsu, H. M. Y. T. K. Matishita, Kobayashi K. Miyasaka, suppression M. and The TBI withchemotherapy, of or modifiers, biological response metastases thechange hostimmune and in after low-dose response whatis theeffect sequence of immunotherapy. Similarly, irradiation tumor-bearing Radiat.Res. 151,717rats. in total-body andinterval between low-dose TBI andother on 724 (1999). drugs the effects? immunomodulatory 10. Y. HosoiandK. Sakamoto, effect lowdosetotal of Suppressive body irradiation lung on metastasis: dependency effective dose and the effects period. Clinically, relating immune-enhancing oflowRadiother.Oncol. 26, 177-179 (1993). dose TBI to itsusefulness mostcritical. is Low-dose TBI 11. Y. Hosoi,K. Ishii,S. Yamada, Ono and K. Sakamoto, T. Effect of is an attractive theoretically and treatment mopromising combination treatment 15 cGytotal of and bodyirradiation OK-432 fornon-Hodgkin's not dality on spontaneous metastasis mitogenic lymphoma, onlybecauseof and of lung response splenoitsproven effectiveness also becauseit appears probut to cytes in mice. Radiat. Oncol. Invest.5, 283-288 (1997). Essential Oxvide an alternative of cancer 12. I. Roitt, Science, Immunology, 380-398.Blackwell pp. mechanism(s) action against 1997. ford, cells. One should welcome factthat newEORTC is the a In J. Tumour (I. immunology.ImmunologyRoitt, Brostoff in low-dose TBI is beingcompared 13. P Beverly, beingdesigned which andD. Male,Eds.),pp. 20.1-20.11. 1998. London, Mosby, to low-dose TBI plusinvolved-field in radiotherapyearly- 14. I. Roitt, Essential Blackwell OxScience, Immunology, 168-178. pp. 1997. stage(I and II) low-grade non-Hodgkin's lymphoma paford, tients. thisstudy, question how low-doseTBI In the of 15. I. Roitt, Essential OxScience, Immunology, 179-199.Blackwell pp. 1997. ford, works being is addressed thefirst for time. relationship The Essential Oxbetween Science, low-dose andthedirect TBI Immunology, 210-221.Blackwell and/or indirect induc- 16. I. Roitt, pp. 1997. ford, tionofapoptosis therelationship t(14;18)andoverand to 17. R. E. Anderson I. Lefkovits, vitro and In evaluation radiation of of It be expression BCL2 willbe studied. would interesting of Am. induced augmentation theimmune response. J. Pathol.79, if such a largemulti-institutional could includethe trial 456-461 (1979). of either known or 18. C. Spellman R. E. Anderson, dose radiosensitivity study someof theimmune parameters and Low of alloimmune cells.J.Exp.Med. 155, 1858-1863 cytotoxic (1982). to TBI, suchas those thought be stimulated low-dose by 19. A. Fourquet, L. Teillaud, LandoandW.H. Fridman, J. D. Effects of studied Yonkosky al.. et by human interleukinlow dose total bodyirradiation recombinant and Muchexperimental clinical and research stillneeded. is 2 in mice.Radiother. Oncol.26, 219-225 (1993). So far, there enough is evidence suggest low-dose 20. S. Z. Liu,Radiation to that hormesis:newconcept radiological a in science. TBI can be immune-stimulatory, it can inducea and that Chin. Med. J. (Engl.) 102, 750-755 (1989).

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COMMENTARY
30. S. Z. Liu,W.H. Liu andJ.B. Sun,Radiation hormesis: expression its in theimmune Health 52, Phys. 579-584(1987). system. 31. K. Ishii, Yamaoka, Hosoi,T. Ono andK. Sakamoto, K. Enhanced Y. ofrat wholemitogen-induced proliferation splenocytes low-dose by Physiol.Chem.Phys.Med. NMR 27, 17-23 body X-irradiation. (1995). 32. S. C. Carabell, T. Chaffey, S. Rosenthal, C. Moloney J. D. W. and S. Hellman, Results total of in of bodyirradiation thetreatmentadvanced Cancer43, 994-1000(1979). lymphoma. non-Hodgkin's 33. H. D. Brereton, C. Young D. L. Longo, comparison R. and A between combination and chemotherapy total bodyirradiation combinaplus tionchemotherapynon-Hodgkin's in Cancer43, 2227lymphoma. 2231 (1979). 34. N. C. Choi,A. R. Timothy, D. Kaufman, W. Carey A. C. R. S. and Low whole irradiationthe in treatAisenberg, dosefractionated body ment advanced of Cancer 1636-1642 43, non-Hodgkin's lymphoma. (1979). 35. W. J.De Neve,M. L. M. Lybeert J.H. Meerwaldt, and Low-dose totalbodyirradiation non-Hodgkin's in short long and lymphoma: term and factors. J. Clin.Oncol.13, 280Am. toxicity prognostic 284 (1990). 36. D. M. Yonkosky, I. Feldman, S. Cathcart S. Kim,ImM. and E. of in provement in-vitro mitogen proliferative responses non-Hodgkin'slymphoma to total patients exposed fractionated bodyirradiation.Cancer42, 1204-1210(1978). 37. Y. Takai, Ogawa,S. Yamada K. Sakamoto, Y. and Two-color analysis of peripheral bloodlymphocytespatients malignant in with tumours after dose halfor total low a bodyirradiation:pilotstudy. Nippon Gakkai 24, 1288-1295 Shi Gam Chiryo (1989). [inJapanese] 38. E. Clave,G. Socie,J.M. Cosset, P. Chaillet, Tartour, GirM. E. T. H. E. and MulE. inski, Carosella, Fridman, Gluckman C. Mathiot, ticolor cytometry flow of in analysis bloodcellsubsets patients given total before bonemarrow Int. bodyirradiation transplantation.J.Radiat.Oncol.Biol.Phys. 881-886(1995). 33, 39. E. T. Bloom, Akiyama, Kusunoki T. Makinodan, M. and Delayed Y. effects low-dose of radiation cellular on in bomb surimmunityatomic vivors in States. Health 52, residing theUnited Phys. 585-591(1987).

in 21. S. Z. Liu,Z. B. HannandW. H. Liu,Changes lymphocyte reaclow radiation. to factors tivity modulatory following dose ionizing Biomed. Environ. 7, 130-135(1994). Sci. 22. R. N. Shen,L. Lu, G. S. Feng,J.Miller, W. Taylor H. E. M. and Cure low-dose total of Broxmeyer, with bodyirradiation thehemain mechdisorder induced micewith Friend virus: tological possible anisminvolving and interferon-gamma interleukin-2. Lymphokine Res. Cytokine 10, 105-109(1991). 23. R. N. Shen, Lu, M. A. Harrington,Srivastava, J.Kim,S. Z. L. C. Y. of and Effect split low Zhou,B. Wu,S. Ruscetti H. E. Broxmeyer, dosetotal on DNA andprobodyirradiation SFFV mRNA, genomic tein in with virus Leuexpression miceinfected theFriend complex. kemia 225-229(1991). 5, 24. S. Z. Liu, SuXu,Y. C. Zhangand Y. Zhao,Signaltransduction in after Chin.Med. J. (Engl.) 107, lymphocytes low dose radiation. 431-436 (1994). 25. M. Nogami, T. Huang, T. Nakamura T. Makinodan, cells J. L. and T arethecellular of effect of target theproliferation-augmenting chronic low-doseionizing radiation mice.Radiat.Res. 139, 47-52 in (1994). 26. M. Nogami, T. Huang, J.James, M. Lubinski, T. Nakamura J. S. J. L. and T. Makinodan, Mice chronically to exposed low dose ionizing radiation with levelsofHSP70 mRNA, possesssplenocytes elevated an to HSC70 andHSP72 andwith increased Int. capacity proliferate. Biol.63, 775-783(1993). J.Radiat. 27. M. Nogami, T. HuangandT. Makinodan, J. of Splenocytes old mice do notrespond thehormetic to effect chronic dose ionizing of low In radiation. Low Dose Irradiation Biological and MechaDefence nisms Sugahara, A. SaganandT. Aoyama, L. (T Eds.),pp.409-410. 1992. Medica, Excerpta Tokyo, 28. M. Galdiero, Cipollarode G. M. A. l'Ero,A. Folgore, Capello, Giobbe andE S. Sasso,Effects irradiation on alterations cyof doses in tokine releaseby monocytes lymphocytes.Med. 25, 23-40 and J. (1994). 29. Y. IbukiandR. Goto, Enhancement concanavalin of A-induced proliferation spleno-lymphocytes of bylow-dose-irradiated macrophages. J.Radiat. Res. (Tokyo) 83-91 (1994). 35,