Prolongation of Murine Skin Allograft Survival by the Systemic Effects of 8-Methoxypsoralen and Long-wave Ultraviolet Radiation (PUVA)
Richard D. Granstein, M .D ., Lauren Smith, and John A. Parrish, M .D . Wellman Laborato ry, Department of Dermatology, Harvard Medi cal School and Massachusetts General Hospita l, Boston, Massachusetts, U .S. A.
Systemic administration of the photoactive drug 8-meth greater inflammati on than the PUV A protocol. All o oxypsoralen to a group of mice bea ring cutaneous allo graft ed, PUV A-trea ted animals also demonstrated de grafts , followed by exposure to long-wave ultraviolet ra creased alloantigen reactivity against donor-strain spleen diation (UV A, 320- 400 nm) (PUVA) dail y for 14 days at cells during the period of treatment by cytotoxicity assays. a site distant from the allograft, si gnificantly in creased the Allografts of skin in the murine system are highly im survival time of the allografts. This effect w as seen both munogenic and are generally rejected faster than organ al in donor- recipient combinations that differ at the major lograft s; thus PUV A treatment appea rs to exert a potent histocompatibility complex and in those differing only at effect on prolonging allograft survival. T he systemic nature minor histocompatibility loci. Trea tment with 8-meth of the effect and the fa ct that adverse side effects from oxypsoralen or long-wave UV radiation alone was inef PUV A are largely limited to the skin suggest that PUV A fec ti ve in prolonging allograft survival, as were doses of might have a role in clinical organ transplantation man mid-wave UV radiation (UVB, 280-320 nm) that produced agement. J In vest Dermatol 88:424-429, 1987
he use of the photosensitizer 8-methoxypsoralen (8- adverse side effects to date. Short-term side effects include ery M O P) in combination with long-wave UV radiation themogeni c res ponses similar to sunburn when the dose of UV A (UV A, 320-400 nm) (known by the acronym PUV A) radiation is not ca refully controll ed, and an apparently idiosyn has gained wide acceptance in medi cal practi ce for the chratic response consisting of a painful or itchy sensa ti on in th e treatment of a number of dermatologic conditions, skin some hours after trea tment. More se ri ous side effects consist Tmost notably psorias is and the cutaneous lymphoma, mycosis of a somewhat increased ri sk of nonmelano ma skin ca nce r de fun goides [1-4]. Psora lens are linea r three-ring heterocyclic com velopment aft er hundreds of PUV A trea tments, primaril y in pa pounds that intercalate between DNA and RNA base pairs in th e tients previ ously trea ted with an additional carcinogen, usuall y dark. T hey can then photo react with the 5, 6 double bond of ionizin g radiati on l4,11], and clinical " aging" of the skin con pyrimidines in the presence of UV A radiati on to yield cycloa d sisting of hyperpigmentati on, lentigo formation, and wrinkling. di tion products [5]. Bo th the furan and pyrone ends of the mol The mechanism of acti on of PUV A therapy is unknown bu t ecul e ca n react; thus cross-links as well as monoadducts are in is pres umed to relate to an inhibition of DNA synthesis second ary troduced into DNA and RNA [6-9]. Although these lesions ca n to photoinduced DNA cross-linking [1] . Numerous cellular and be mutageni c or cytotoxic [1 0), the wides pread use of PUV A animal studies have been performed to evaluate the biologic effects therapy in cl inical medicine has been associated with acceptabl cr of PUV A trea tment. These include a systemic suppression of the ability to sensitize mice to contact sensitizers, accompanied by the appea rance of splenic antigen-specific T suppressor cells [1 2,13]. A similar effect on the inducti on of sensitivity to the topical Manuscript received August I, 1986; accepted for publica ti on Octo ber all ergen dinitrochlorobenzene (ONCB) has been described in hu 24, 1986. mans with psorias is [1 4]. T his in vesti ga ti on involved exposure T his work was suppo rted by N ational Institutes of Hea lth C linica l In vesti gator Award AM01 425-02 and a grant fro m the Arthur O . and of both the site of sensitiza ti on and distant sites to PUV A; there Gullan M. Wellman Foundati on. fore, differentiati on of local from systemic effects w as not pos Reprint reques ts to: Richard D . Granstein, M .D., Department of Der sible. T his study also demonstrated some diminution in the elic matology, Massachusetts General H ospital, Boston, Massachuse tts 0211 4. itati on res ponse to ONCB in previ ously sensiti zed psoriati c patients. Abbreviatio ns: Additionall y, PUV A has been demonstrated to decrease the num Con A: concanava lin A ber and perturb the morphology of the antigen-presenting cell of CTL: cytotoxic lymphocyte the epidermis, the Langerhans cell (1 5). Inves ti ga ti ons examining O N CB: dinitrochl o robenzene the phenotype of peripheral bl ood lymphocytes in patients ex FCS: fetal ca lf serum posed to A have demonstrated that a single erythemogeni c MHC : maj or his tocompatibility complex ruv 8-M OP: 8-methoxypsoralen expos ure to PUY A results in a decrease in circul ating T cells and PUV A: psoralen plus UV A B cell s, with an increase in the proportion of cell s w ithout B or SC: spl een ce ll (s) T markers [1 6]. Pati ents with psori as is exposed to long-term UV A: long-wave ultraviolet PUY A trea tment have been demonstrated to have a decreased UVB: mid-wave ul traviolet number of circulating helper pheno type (T4 +) T cell s [1 7]. These
0022-202X/87/S03.50 Copyrig ht © 1987 by T he Society fo r Investigative Dermatology, Inc.
424 VOL. 8H, N . 4 A J>IU L 19H7 PR O LO N GA T IO N OF ALLOGRAFT SURV IVAL BY PU VA 425
va ri o us o bserva ti o ns suggest that PUVA treatm ent may have Scoring of Graft Rejection G rafts were examined dail y in a immuno logic consequences that could have therapeutic impli coded fas hi on and rej ecti o n w as scored w hen 50% of the area of ca ti o ns. the graft had undergone necro ti c degenerati o n as assessed by vis Earlier repo rts ha ve demo nstrJted til Jt preexposure of all ografts ual inspecti o n of the g rafts. Differences in survival among gro ups to PUV A therapy 11 8,1 9J o r local exposure of the site of skin was assessed by the rank-sum test. graftin g pro lo ngs all ograft surviva l [201. Because preex posure o r Cytotoxicity Assay Recipient mice were sacrifi ced and a mo n loca l exposure of an all ograft to PUV A mig ht produce dJ mage ocellular suspension o f nucleated spleen cell s (S ) was prepared. of fun cti o nal significa nce, and because irradiati o n of an internal Spl een cell s fro m graft recipients were restimulated in vitro by a organ in situ is no t practi cJI , we have eXJmined the ro le ofPUVA meth od similar to that of Burako ff et al [22]. BrieAy, 7 X 106 th erapy o f the recipient in modi fy ing all ograft rejecti o n. responder S were cocultured w ith I X lO r. erythrocyte- free x We present here data demo nstrating that PUV A therapy of irradiated ( 1500 R) stimulator do no r-strain splenocytes in '16-mm graft recipients markedl y prolo ngs the surviva l of skin all ografts ti ssue culture well s (Linbro; Fl o w Labo ratories, In c., M cLea n, at a non irradiated site in geneti ca ll y defin ed mice both w hen the Virginia). ulture medium consisted ofHPMl1 640 supplemented dono rs and recipients differ at loci of the majo r histocompatibility w ith 10% heat-inacti vated fetal ca lf serum (FC S), antibio ti cs (100 co mplex (MHC), and when onl y mino r histocompatibility dif U / ml penicillin and 100 fL g/ml strepto m ycin) , 2 I1lM L-glutamine, ferences arc present. The systemic natLIre of the effect suggests I mM sodium pyruvate, nonessential amino acids (0.1 mM of that it may be usefu l in prolo ngin g the survival o f internal o rg:lI1 each), and 5 X 10 - 5 M 2-merca ptoethano l. ultures were in cu transplants. bated fo r 5 days at 37°C in a humidified atmosphere containing 5% O 2 . MATERIALS AND M ETHODS Chromium Release Assay yto toxicity o f effector cell s was Laboratory Animals Female BALBlc (H_2d), 57BLl6 (H- assessed by using do no r-strain conca navalin A ( on A) lympho b 2 ), A/j (H-2"), and B 10. A/ SgS nj (1-1-2") mice were o bta ined fro m blasts as ta rgets. Concanavalin A blasts w ere prepared by a 2-day the Jackson Labo rato ry (Bar Harbo r, Maine) . A /J and n 10. A/SgSnJ culture of2 X 107 SC in 10 ml of medium containing 2.5 fL g/ ml mi ce di ffer at a number of mino r histocompatibility loci including of on A (S ig m a hemica l Co., St. Lo uis, Missouri). Labeling H- l , 1-1-3, 1-1-4, H-7, and H-8. T he animals were 8-14 weeks old at th e start of each experiment and w ithin each experiment the age of the animals did not vary by mo re than 2 weeks. T he mice had fr ee access to Purina M o use how and chl o rinated water and 100 were housed in a fac ility where ambient li ght w as regul ated on -' ~ a 12-h li g ht/ dark cycle. > It: 80 ::> Skin Grafting Skin g raftin g was perfo rmed by the method of Fi sher and Kripke 1211· T he truncal skin of dono r mice w as shaved ~ II.. 60 and chemica ll y depi lated (N eet, Whitehall LaboratOries, N ew York, of blast cell s was performed by in cubation of 2 X 107 recovered diati on (PUV A) . Trcatmcnt was begun 1 day after graftin g and cell s w ith 150 j.(.1 o fNa5 1C r04 (2 mCi/ ml; N cw E ng land Nuclea r, continued for 14 d ays. T his regimen res ulted in o nly mild scaling Boston, Massachusetts) for 90 min. and hypcrkeratosis of PUVA-exposed skin sites by day 14. Mice The isotope rei case assay was perfo rmed in ro und-botto med were cxam ined daily for g raft rej ection. Figure 1 A shows that microtitcr platcs (Dynatech Laboratories, Al exandria, Virg ini a) recipicnts treated w ith PUV A have significa ntly longer allog raft by the addition of se ri al d ilutions of effector ccll s to 1 X 104S I Cr_ surviva l compared w ith other gro ups (p < 0.01, PUVA g roup labeled ta rgct cell s in a total volumc of 200 j.(.1 minimal cssential compared with the other g roups). 8-Methoxypsoralen o r UV A medium containing 5% FCS. T he platcs were ccntri fuged (300 radiation trea tment alone had no effect o n all ograft survival time. g, 30 s) at thc beginning of thc assay, incubatcd at 37"C for 3-4 These results w ere confirmed in the additio nal experiment shown h, and centrifugcd again (500 g, 10 min). A volumc o f 100 j.(.1 o f in Fig 1 B. Figure 2 contras ts a rej ected graft fro m the untrea ted m edium was rcm ovcd from each wcll for ga mma counting. Pcr group (right) w ith an essentiall y intact graft fro m the PUV A cent spccifi c chro mium-51 release was computcd according to thc g roup at day 19. As a technica l contro l, 6 A /J mice were grafted fo rmula (E - S)/(M - S) X 100%, in w hich E is thc isotope w ith isografts; these g rafts all survived indcfinitely. Also, 3 11 0 - rclease in thc p rcsence of effector cells, S is the spo ntaneous iso g raftcd mice trea ted with this rcgimen but witho ut hair rem oval tope rei case in the presence of medium, and M is the m aximal had no pro lo nga ti on of g raft surviva l. T hus, any stray li ght reach releasc obtain ed by adding to thc targets an eq ual volume of 1% in g thc graft could not account fo r our findings. Triton x-tOO. The results are reported as the mea n percent spe Prcliminary data (not shown) indica te that this PUV A protocol cific rel ease of duplica te meas uremen ts w ith negative determi does not inhibit the dcvelopmen t of contact h ypersensitivity to nations reported as O. dinitroflu o robcnzene when it is applied to a nonirradiated site ] h after thc 14th P UVA exposure with eli citation 7 days later. It RES ULTS is currcntly un known w hethcr this pro tocol would suppress the Effect of PUV A Treatment on Survival of MHC-Incom induction of contact hypersensitivity if started at the timc of or patible Cutaneous Allografts at a Nonirradiated Site To just aftcr immuniza ti on. examine the possible ro le of PUV A in the pro longation of all o Effect of UVB Radiation on Survival of MHC-Incompat graft survival, A /J mice (H-2") were g rafted on the do rsum with d ible Cutaneous Allografts To exam inc the specificity of the cutaneous all ografts from BALBlc donors (H_2 ). A/J and BALB/c PUV A cffcct o n allograft surviva l, an cxperiment was designed mice differ at m any loci of the MHC. T he g rafted mice were to cxa minc w hether equall y inflammatory doses ofUVB radiation divided into the fo ll owin g groups: g roup 1, no trea tment; g ro up would have any effect o n all ograft surviva l. Ultraviolet B radi a 2, adm inistration 'of 8-MOP; g ro up 3, ex posure of the ventral tion (280-320 nm) is thc waveband responsible for m ost of the surface of thc animals to UV A radiation (1500 J/ m2); and gro up crythem ogcni c res po nse to natural sunlig ht [231. Preliminary ex 4, ad ministratio n of 8-MOP fo llowed by cxposure to UV A ra- pcrimcnts detcrmined that 3600 J/ m2 of UVB radiation from FS40 sunlamps had approximately thc sa m c inflammatory effect on AI] micc as l 500 J/m 2 in o ur PUVA pro tocol after sevcral ex posures (data not shown). A/J mice w ere g rafted o n the do rsul11 with BALBlc skin and d ividcd in to 2 groups. O nc g roup received 2 daily UV B exposure (3600 J/ m ) to the ventral surface for 14 da ys starting 1 day after grafting, while the o ther gro up was untrca ted. Fig ure 3 c1ca rl y shows that this UVB rad iatio n trea tment had no cffcct on all ograft survival. An additio nal experiment was per fo rmcd usin g a dose of UVB rad iation sufficient to cause crusting and supcrfi cial erosions at irradiated sites by 14 days. Twelvc A/J micc wcrc g rafted with BALBlc skin o n the dorsa l surface and divided. O ne group received 5400 ]l m 2 of UVB irradiation to thc ventral surface dai ly for 14 days as above, w hile the other ...J 100 ~ > 0:: 80 ::J (/) ..... I&.. 60 4 0:: (!) ..... 40 z IIJ 0 0:: 20 L&J CL. 0 9 10 II 12 13 14 15 16 DAYS AFTER GRAFTING Figure 3. Cutaneous all ograft survi va l. AI) mice were grafted with BALB/c Fig ure 2. AI) mice grafted with BALBlc sk in . Esscntiall y in tact graft sk in. Treatment of recipi ents: ope" sq"nres, no trea tment (n = 5); ope" on PUV A-treated mouse (leji) co ntras ted with a rejected graft on an circles, UV B radiation ex pos ure (n = 5). No signi fica nt difference in the untrcated mouse ( , · (~ /Il ) . surviva l of the all ografts wa s seen between the two groups. VOL. 88, NO.4 APRIL 1987 PRO LONGATION OF ALLOGRAFT SURVIVAL BY PUVA 427 Table II. Cytotoxicity of Recipient Spleen Cell s (SC) Against ...J 100 C57BLl6 T argets ~ :; Percent Specifi c a: 80 :::l Lysi " (I) PUVA Immuniza tio n with I- LL. 60 G ro up" Treatl11 cnt" C57BLl6 SC' EfT: 33: 1 11:1 c( a: (!) + 44.5 33.4 I- 40 2 44.3 29.6 z + + L&J 3 N o ng raftcd. 11 .4 6.2 0 a: 20 nomrcatcd (neg contro l) L&J Q. ·' A /j mice were grarted with BALBlc skin in groups I and 2. 0 "PUV A trea tment as in footnote to T:lblc I except treattnent W:1S continued daily 6 8 10 12 14 16 18 20 22 24 26 fo r 14 da ys. (Five days after the last PUVA trC:1tm cnt. thc mice were injected with 3 X 107 DAYS AFTER GRAFTING eryth rocyte-free, x-irradiated 57BLl6 SC subcutaneously. Seven da ys arter il11 - 1t1lIlliz:ltioll . mice Were sacrificed and assays begun . Restimulatioll was with C57BL/6 Figure 4. C ut~n eo u s 311 0gr3ft surviva l. Af] mice werc g r~fted w ith B IO.A Sc. skin. Trc3tmcnt of recipients: OpCII sqllm·cs, no treatment (n = 6) ; OpCII JTa rgcts were C5713L/6 concall:1va lin A bla sts. Spontaneous isoto pe release \vas circles, 8-M O P plus UVA radiation (PUVA) (n = 7) . T he surviv3 1 of < 25%. grafts in the PUV A group was signifi ca ntly prolonged compared to the oth er gro ups (p < 0.0 1). less cytotoxic activity against BA LB/c targets compared with cell s fro m gr3fted, non-PUV A- treated mice. In fact, the cell s from group was untreated. T his dose of UVB radiation also fa il ed to PUV A-treated mice show less activity than the negative control; prolong all og raft survival (mean survival ± SEM for the treated thc cytotoxicity seen in thc negative groups m ay be grea ter than group 16.6 ± 0.9 days vs 14.2 ± 1.4 days fo r the control). zcro due to som e in vitro priming during the 5-day culture period. To exa mine the immunocompetence of an imals after a course Effects ofPUV A on Survival of Minor Histocompatibility of therapy, gro ups of PUV A-treated and non-PUV A-treated AI] Disparate C utaneous A llografts AI] (H-2') and B10.A (H- micc bearing BALB/c skin grafts were immunized to C57BLl6 2') mice are MHC-identica l but differ at a number of minor SC, 5 days after the treated group fin ished a 14-day course of histocompatibili ty .Ioci. In the fo ll owin g experiment, AI] recip PUV A-therapy. In agreement w ith the data shown above, the ients were grafted on the dorsum w ith B10.A skin. T he grafted trea ted group Iud significantly longcr all ograft survival comparcd mi ce w ere d ivided into 2 treatment gro ups: gro up 1, no trea tment; with the untreated control group (dat3 not shown)'. Seven days group 2, administration ofS-M O P fo ll owed by exposure to 1500 latcr, mice were sacrifi ced and a C TL assay performed as 3bove 2 Jl m of UV A r3d iation (PUV A). As above, the mice were trea ted against C57BLl6 targets. The data in Table " show that by 5 dai ly for 14 days st3rti ng 1 day after grafting, and they were days 3fter the end of PUV A tfl er3py, trea ted graft recipients are exa mined da il y fo r graft rejecti on. Fi gure 4 cl ea rl y shows that able to be both scnsitized w ith and express immunity to a new recipients tre3 ted with PUV A have signi fi c3 ntf y prolonged al all oantigen. lograft surviva l compared to controls. Grafted Mice Treated with PUVA Demonstrate Decreased DISCUSSIO N Splenic Cytotoxic Activity Against Donor-Strain Targets To examin e antidonor cytotoxic activity, some AI] mice bea rin g T hc understanding and management of transplantation and graft BALB/c skin grafts were s3cri ficed on day 7 of PUV A therapy, toler:\I1 ce arc areas of great importance in cf inicalmedi cin e. Dem 2 h after the 7th PUV A treatment along w ith non-PUV A-treated onstration of the essential role of ly m phocytes in graft rejection controls for cytotoxic lymphocyte (CTL) ass3ys. Host spleno dates back to the ea rl y work of Medawar and his associates 124,25]. cytes were restimubted in vitro fo r 5 days in the presence of Transplal1tation managem ent is gener311 y conducted by suppres donor-strain nucleated Sc. Stimulated splenocytes were then tested sion of the host immune system to all ow graft tolerance. T hree for their ability to lyse dOll o r-strain t3rgets in a 4-h chromium- bas ic approaches have bcen uti.Ii zed : (1) drug-induced immuno 51 release assay. T he d3ta in Table I show that splenocytes h3r suppression; (2) total ly mphoid x-irrad iation; and (3) anti-T-cell ves ted from 3]J ografted, PUVA-trea ted m ice have substantiall y antibody therapy. Although both irradiation and drug immu nosuppression therapies have proved successful in the manage m ent of closely matched grafts r26-28], they have proved less reli able in less closely m atched grafts, at least in regimens not Table I. C ytotoxicity of Recipient Spleen ells (SC) Again st usin g cycfosporin [29], and present many undesirable side cffects BALB/c Targets 3S a rcsul t of their b ck of specifi city. Anti-T-cell antibody therapy is in its infancy, 31tho ugh its relative specificity suggests the pos Percent Spcciflc Lysis' sibility of certain adv3ntagcs, particul arl y with regard to side effects. Group" PUV A Treatment" EfT: 33 : I II: I T his report demonstrates that PUV A treatment systcmicall y 46. 7 27.4 prolongs the surviva l of cutaneous all ografts both when the do (pos contro l) nor-recipient combination is mism atclwd at the MHC and w hen 2 + 12.2 3. 1 onl y minor hi stocompatibility differences are present. Decreased 3 N ongraft ed , no ntrea tcd 22.9 7.7 reactivity of the host against graft determinal1ts was confirmed (neg control) with the CTL assay. T he effect of PUV A treatm ent was seen ' A /j mice were g rafled with BALBlc skin in groups I and 2. despite the fact that no therapy was administered beyond day 14 ' PUVA-trca ted recipients wcre g ivcn 0.4 nt g ofS-MO P in 0.2 Illi of a 2% gelatin after graftin g. T he systemic nature of this effect is of great im solution by i. p. injecrion dail y for 7 da ys starting 24 h after g raftin g. Fifteen minutes portance; it suggests that PUV A treatment might also be useful 2 aft er injectio n. the shaved ventra l surrace of cach 311 im :1 1 was exposed to 1500 J/ m in prolonging the survival of all ografts of internal organs. As of UV A radiation. A ll mice were sacrificed and assays begun 2 h after the 7th PUV A exposure. Res tirnnlation was w ith BAUVc Sc. mentioned previo usly, a grea t deal of experience has been clini (Ta rgets werc DALE/c blasts. Spontaneous isoto pe release was < 25(¥o. call y obtained w ith PUV A in the trea tment of va ri ous skin dis- 428 G RANSTEIN, SMIT H , AND PARRISH T H E JO URNAL O F IN VESTIGATIVE DERMATOLOGY eases 11 -4] and undesirable sid e effe cts ha ve been accepta ble and 7. Da ll ' Acq uJ F, Marciani S, Rodi ghicro G: In terstrand cross-linkages limited to the skin . Indeed , th e direct effects of PUV A therapy occurring in thc photoreaction bctwce n psoralclI and DNA. FEBS are limited to the depth o f penetration of the UV A radiation Lett 9: 12 1- 123, 1970 photons (essentially restricted to the skin in humans) . This sug 8. Isa acs ST , Shcn CK), Hca rst JE , Rapoport H: Synthesis and char gests that, if PUV A proves to be a useful adjuvant modality in acterization of ncw pso ralcn dcrivatives with superi or photoreac the m anagement of organ transplants, it may be rel ati vely fr ee tivity w ith DNA and RNA. BiochcmistryI6:1058-1064, 1977 fro m serious systemic adverse effects. A sa fe adjunctive therapy 9. Wo ll enzicn PL , You van DC , Hcarst JE: Structurc of psoralen-cross may be quite useful in reducing th e dosage of other elements of linked ribosomal RN A from Drosophila lIIe1allogastcr. Proc Natl a th erapeutic regimen to reduce adverse side effe cts and, of course, Acad Sci USA. 75 :1642-1646, 1978 to enhance the efficacy of the regimen. Such studies are in progress 10. Scott BR, Pathak MA , Mohn GR: Molccular and genetic basis fo r in animal m odels. It is important to note, however, that other furocoumarin reactions. Mutat Res 39:29-74, 1976 modalities of chronic immunosuppression in humans are asso 11. Stern RS , Laird N , Melski), Parrish JA, Fitzpatrick TB, Bleich HL: ciated with an increased risk of skin ca ncer [30-36); since PUV A Cutaneous squamous-cell carcinoma in paticnts trea ted with PUV A. is a cutaneous ca rcin ogen [4,11] the use of PUV A in co mbinati on N E nglj Mcd 310: 1156- 11 61,1 984 w ith other immunosuppressive agents m ay lead to an in creased 12. Kripke ML, Mori son WL, Parrish )A: Systemic supprcssion of Con ri sk of skin ca nce r even if PUV A all ows for small er dosages of tact hyperscnsitivity in mice by psoral en plus UV A radiation these other agents. (PUV A). ) In vest Dermatol 81 :87-92, 1983 T he m echanism of action of PUV A in prolongin g all ograft 13. Mo ri son WL: In vivo effccts of psoral cns plus longwave ultraviolet survival is unknown. Although a lack of reactivity of the host radiation immunity. Nat! Cancer Inst Monogr 66:243-246, 1984 again st g raft determinants is evident, we have not established 14. Moss C, Fricdmann PS , Shuster S: Impaired contact hypersensitivity whether this res ults from a fai lure of sensiti za tion or down-reg in untreated psoriasis and thc effects of photochemotherapy and ulation of the effe ctor and o f the immune res ponse. A number dithranoI/ UV-H. Br j Dcrmatol 105 :503-508, 198 1 of hypotheses may account for the activity of PUV A in sup 15. Nordlund)J, Ackl es AE, Lerner AB: The effects of ultraviolct li ght pressing rejecti on of the allografts. PUV A may, by virtue of and ce rtain drugs on la-bearin g Langcrhans ce lls in murine epi inducin g infl ammation, alter the traffickin g patterns of immu dermis. C ell Immunol 60:50-63, /981 nocompetent cells with functional consequences. However, the fa ilure of doses of UVB radiati on that produce grea ter cutaneous 16. Mo rison WL, Parrish jA, Block KJ, Krugler )1 : In viv o effects of PUVA on lymphocyte fun cti on. Br) DermatoII 04:405-413, 1981 infl ammation than the PUV A doses used in these studies to have an effect on graft survival would argue against a simple ca use and 17. Moscicki RA , Mo ri son WL, ParrishJA, Bloch K), Colvin RB: Re effect relationship between inflammati on and the immuno duction of the fra ction of circulating helper-inducer T cells iden tified by monoclonal antibodies in psoriatic p;lticnts trea tcd with suppression o bserved . PUV A therapy may directly affect lym long-term psoralcn ultraviolct-A radiation (PUV A) . J In vest Der phocytes as they circulate through the microvasculature of the matol 79:205-208, 1982 skin , ca usin g them to be perturbed in such a way that they ca nnot 18. Gruner S, Riesc C, Schnitzler S, Meffert H, Karasck E: Prolonga tion be sensitized to all oantigens. An additional possible mechanism of the surviva l of sk in grafts in mice by PUV A treatment. Ex would in volve the rel ease of a mediator(s) by targets in th e skin pericntia 40:487-488, 1984 affected by PUV A that circulate and render the host immune system unable to recogni ze and/or be activated by all oantigens. 19. Osterwitz H, Scholz D, Kaden), Mebel M: Prolonga tion of rat renal all ograft surviva l timc by donor pretrea tment with 8-mcthoxy At this time, there is no direct evidence supporting any of these psoralen and longwavc ultraviolet irradiation of the graft (PUVA hypotheses. Of course, PUV A m ay be exerting more than one therapy). Urol Res 13:95-98, 1985 relevant effect. C utaneous all ografts are hi ghl y immunogeni c; they are gen 20. Morison WL, Parrish JA, Woehler ME , Bloch KJ: The inAuence of }JUV A and UVB radiation on skin graft survival in rabbits. ) erall y rejected faster than organ all ografts [37]. 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