IMMUNODEVIATION BY PASSIVE ANTIBODY, AN EXPRESSION OF SELECTIVE IMMUNODEPRESSION II. ACTION OF GUINEA PIG IcG1 AND IGG2 ANTICARRIER ANTIBODIES

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1 IMMUNODEVIATION BY PASSIVE ANTIBODY, AN EXPRESSION OF SELECTIVE IMMUNODEPRESSION II. ACTION OF GUINEA PIG IcG1 AND IGG2 ANTICARRIER ANTIBODIES BY PHILIPPE VUAGNAT, THI~R]~SE NEVEU,* AND GUY ANDR]~ VO1SIN:~ (From the Centre d'immuno-pathologe et d'immunologe JExp~rmentale de l'assocaton Claude-Bernard et de I'I.N.S.E.R.M., H 3ptal Sant-Antone, Pars, France) (Receved for publcaton 23 May 1972) The phenomenon of mmune devaton (1), also termed splt tolerance (2) or contrasenstzaton (3), seems to be of crucal mportance n tryng to understand the relatons between the two phenomena of mmunologcal facltaton (enhancement) and mmunologcal tolerance (4). Its mechansm s possbly due to a selectve mmunodepressve acton of varous mrnunoglobuln classes of antbodes on actve antbody producton of varous classes. The precedng artcle has ndeed shown the dfferental effect of passve IgG1 and IgG2 anthapten antbodes on the antbody producton of these two classes, the man fndng beng the delayed enhancng effect of passve IgG1 on ther own producton. 1 On the other hand, hapten-carrer relatonshps have been reported n several mmunologcal systems and, more recently, nterpreted wthn the frame of T cell-b cell cooperaton (revewed n 5). Immunzaton of the gunea pg wth a hghly hapten-substtuted carrer proten leads to antbody producton aganst the hapten and delayed hypersenstvty to the carrer moety (6). It has therefore been thought of nterest to look for the possble effects of passve IgG1 and IgG2 antcarrer antbodes on the actve IgG1 and IgG2 anthapten response. The present experments carred along wth the precedngly reported ones 1 deal manly wth these effects. As t wll be seen, the observed results are best explaned by postulatng a regulatory functon of the Fc porton of the IgG1 antcarrer antbody, combned wth the antgen, on the T cell. Materals and Methods Anmals.--Anfbody donors and recpents were adult Hartley gunea pgs, of the same orgn and kept together wth those used n experments reported elsewhere. 1 * Partally supported by DGRST (Grant ). :~ Team assocated wth the Centre Natonal de la Recherche Scentfque (E.R.A. 149). 1 Vuagnat, P., T. Neveu, and G. A. Vosn Immunodevaton by passve antbody, an expresson of selectve mmunodepresson. I. Acton of gunea pg IgG1 and IgG2 anthapten antbodes. Eur. Y. Immunol. In press. THE JOURNAL OF EXPERIMENTAL MEDICINE VOLUME 137,

2 266 ANTICARRIER ANTIBODY HOMEOSTATIC FUNCTION Antgens.--Bovne gamma globuln (BGG) 2 and bovne serum albumn (BSA) were dntrophenylated by the method of Esen (7). The conjugated protens were purfed by acd precptaton or by fltraton on Sephadex G-25. The same preparaton of DNP~I-BGG and DNP 6-BSA was used throughout the experments. Subscrpts refer to the average number of dntrophenyl (DNP) groups per proten molecule, calculated from the absorbance at 360 nm and the dry weght. Human gamma globuln (HGG) was separated from Cohn fracton II by DEAE-cellulose chromatography, usng a 0.01 M TIs-HC1 buffer, ph 8.0. Pa,~sve Ambodes.--Gunea pgs were mmunzed as descrbed by Bnagh (8) and bled on day 30. The sera were pooled and decomplemented by heatng 30 ran at 56 C, and alquots were adsorbed on polymerzed HGG (9). Ant-HGG antbodes were eluted wth 0.1 M glycne- HC1 buffer, ph 2.8, wth a yeld of 59%. Pooled eluates were chromatographed on a DEAEcellulose column equlbrated wth M phosphate buffer, ph After collecton of the IgG2 n the effluent, the IgG1 were eluted wth a lnear NaC1 gradent. The fracton eluted between 0.04 and 0.1 M NaC1 was selected. After concentraton to 9 mg/ml, both IgG1 and IgG2 fractons had a tter of 1 : 10,000 by passve hemagglutnaton. The IgG2 fracton had a tter of 1 : 16,000 by passve hemolyss, and of 1:5 by passve cutaneous anaphylaxs (PCA), although no IgG1 could be antgencally detected by the Ouchterlony technque. The IgG1 fracton has a PCA tter of 1:8,000 and a hemolytc tter of 0, even though some IgG2 could be antgencally detected. The relatve avdty of the IgG1 and IgG2 antbodes was found to be smlar, usng the method descrbed by Cerottn et al. (10). IgG1 and IgG2 antbodes were used at the concentraton of 2 #g/ml of 0.15 M borate buffer, ph 8.2, contanng a 1:15 dluton of a hypermmune gunea pg antlovalbumn serum as carrer. [125I]HGG (22 nc/~g) was obtaned accordng to the method of McConahey and Dxon (11). After overnght ncubaton at 36 C n a shakng water bath and samplng, a 300-fold excess of cold HGG was added. Alquots were sampled at gven ntervals thereafter, startng on the 10th ran. IgGl- or IgG2-bound radoactvty was determned by precptaton wth a preheated ant-igg1 or ant-igg2 monospecfc rabbt serum. All determnatons were done n duplcate, along wth the necessary controls. Fnally, sheep red blood cells were coated wth dntrophenylated bovne gamma globuln (DNP51-BGG) by the chromum chlorde method (12). A 1.5% concentraton of CrC18 was found to be adequate. Wth ths antgen, ant-hgg IgG2 were three twofold dlutons less effectve n the passve hemagglutnaton test than purfed ant-bgg IgG2 used at the same concentraton. Immunzaton of Expermental Anmals.--Ths was done under the same condtons and at the same tme as the mmunzaton of the anmals used n prevous experments. I Allocaton of anmals nto groups homogeneous for sex and weght, and allocaton of treatments, was randomzed. Adequate quanttes of DNPs1-BGG and of antbody preparatons were ncubated 60 ran at 37 C n a shakng water bath; then the whole mxture was emulsfed wth an equal volume of complete Freund's adjuvant (Dfco Laboratores, Detrot, Mch.). Each anmal receved 0.2 ml of emulson contanng 25 /~g of antgen and 500 #g of antbody, dvded between the hnd footpads. A booster njecton of 100 #g of antgen n salne was gven on the 12th wk, dvded nto 6 ntradermal stes on the shaved back. Determnaton of Actve Responses.--Serum antdntrophenyl (DNP) IgG1 and IgG2 antbody contents were measured by the modfed Farr method, usng the same reagents and the same condtons as those descrbed elsewhere. ~ Actually, sera from both experments 2 Abbrevatons used n ths paper: BGG, bovne gamma globuln; BSA, bovne serum albumn; DH, delayed hypersenstvty; HGG, human gamma globuln; PCA, passve cutaneous anaphylaxs.

3 PHILIPPE VUAGNAT, TH]~RI~SE NEVEU, GUY ANDR]~ VOISIN 267 were assayed at random and blndly, rrespectve of the treatment a gven anmal had receved. All test sera from any one anmal were assayed on the same day. Delayed hypersenstvty to the carrer was assessed by skn test n four other anmals of each group (nne anmals n the control group recevng antgen alone) on the 5th wk after prmary mmunzaton,.e., at the peak of the anthapten antbody response. 10 and 50/~g of BGG were njected ntradermally 24 h, and Evans blue ntravenously 100 mn, before sacrfce. RESULTS Effect of Passve A ntcarrer A ntbodes on the IgG2 A nthapten Response.--As shown n Fg. 1, passve IgG2 had a unque effect the 1st wk after mmunzaton, the dmnuton of the anthapten IgG2 antbody level beng hghly sgnfcant e~ tu td 2 E r.., z 13o o 1. m 0_ z O 0.5..:" I...4 /...'" /..$" ~ ",......'".~. E / " ~ & / t - + -,= -..,: / S''" "" WEEKS AFTER PRIMARY IMMUNIZATION FIG. 1. Groups of sx gunea pgs were mmunzed on day 0 wth 25 #g of DNPst-BGG ether alone (X... X) or mxed wth 500 /zg of purfed ant-hgg IgG1 (~ x) or IgG2 (Am-A) antbodes. A booster njecton of 100 #g of antgen n salne was gven on the 12th wk (arrow) and serum was obtaned 4 and 10 days later. Actve producton of anf-dn-p IgG2 antbodes was assayed by the Farr method, usng an ant-igg2 monospecfc rabbt serum. Indvdual determnatons were made n duplcate and the mean computed for each group. (P < 0.005, Student's t test). From the 2nd wk onward however, the IgG2 response, although reduced, was the least suppressed of all groups recevng passve antbodes, ether anthapten or anfcarrer. On the other hand, passve mmunzaton wth antcarrer IgG1 antbodes reduces more effectvely the IgG2 anthapten response, and ths to a degree strkngly smlar to the one observed after passve anthapten IgG1 antbodes and reported elsewhere. 1 The latter pont s llustrated n Fg. 2. Effect of Passve Antcarrer Antbodes on the IgG1 Anthapten Response.- Unexpected was the absence, from the 2nd wk onward, of a suppressve effect of passve antcarrer IgG2 antbodes on ths response, as llustrated n Fg. 3. Passve antcarrer IgG1 antbodes however are as suppressve as were passve anthapten IgG2 antbodes, and ths effect s stll seen, although not sgnf-

4 268 ANTICARRIER ANTIBODY HOMEOSTATIC FUNCTION n,, O z 0 m cn.< 0.! g o_ z o x... ~... ~ :,- ~ :" ":':...".o--. _ g_..=_.=~ ':" d" WEEKS AFTER PRIMARY IMMUNIZATION y FIG. 2. Groups of sx gunea pgs were mmunzed on day 0 wth 25 /zg of DNPs]-BGG ether alone (X... X) or mxed wth 500 #g of purfed ant-hog IgG1 (A--A) or ant-dnp IgGt (... ) antbodes. A booster njecton of 100 #g of antgen n salne was gven on the 12th wk (arrow). Ths graph s a combnaton of results presented n Fg. 1 and elsewhere. 1 :E p,. uj u3 g E3 Z 0 O3 0.?! m 025_ Q- Z Q 0 0 H // / --~...,-'-E ~.~... / /.'~,~..'""" ~'"t.8,1"..," ~ g g//2 13 WEEKS AFTER PRIMARY IMMUNIZATION FIG. 3. Groups of sx gunea pgs were mmunzed on day 0 wth 25 #g of DNPs1-BGG ether alone (X... X) or mxed wth 500 #g of purfed ant-hgg IgG1 (A A) or IgG2 (&---A) antbodes. A booster njecton of 100/Lg of antgen n salne was gven on the 12th wk (arrow), and serum was obtaned 4 and 10 days later. Actve producton of ant-dnp IgG1 antbodes was assayed by the Farr method, usng an ant-igg1 monospecfc rabbt serum. Indvdual determnatons were made n duplcate and the mean computed for each group. cant, 10 days after remmunzaton. Ths s the moment (Fg. 4) when the dssocaton between the effects of passve IgG1 antcarrer and anthapten antbodes on the IgG1 anthapten response s most obvous (P < ). Ths dssocaton s one of the bases for the nterpretaton gven n the dscusson.

5 PHIL1]?PE VUAGNAT, Tttl~Rt~SE NEVEU, GUY ANDR]~ VOISIN 269 The data, wth regard to the effect of passve antcarrer antbodes, are summarzed n Table I. Effect of Passve IgG1 and IgG2 Anlbodes on Delayed Hypersenstvty.- Wth the doses of antgen used to skn test the anmals on the 5th wk after pr- mary mmunzaton, no clear-cut dfferences were seen between the expermental groups, whether they had receved passve IgG1 or IgG2 antcarrer or ant- hapten antbodes, although all appeared to be somewhat nhbtory. ~" e,,. E O,.,n ' 0.5. t.9 f_ t r~ '" /"" ~... jr" $... x... ~ /..x....." " f / / t / % / "-4',~..." WEEKS AFTER PRIMARY IMMUNIZATION FIG. 4. Groups of sx gunea pgs weze mmunzed on day 0 wth 25 #g of DNPsz-BGG ether alone (X. X) or mxed wth 500 #g of purfed ant-hgg IgG1 (/k--~) or ant- DNP IgG1 (O... O) antbodes. A booster njecton of 100/zg of antgen n salne was gven on the 12th wk (arrow). Ths graph s a combnaton of results presented n Fg. 3 above and elsewhere. 1 TABLE I Acton of Passve Antcarrer Antbodes on the Itumoral Anthapten Antbody Response After Prmary and Secondary Immunzaton* Actve ant-dnp response Passve ant-hgg antbodes used IgG2 IgG1 Prmary Secondary Prmary Secondary IgG IgG * Prmary mmunzaton conssted of 25 #g of antgen emulsfed n complete Freund's adjuvant wth 500 #g of antbody. Antgen alone n salne was used to boost the anmals on the 12th wk (secondary mmunzaton). :~ The prmary response s expressed as ts surface area untl the 6th wk, relatve to controls taken as 100. Results were compared by Wlcoxon's test. The secondary response s that of day 10 after boostng, relatve to controls taken as 100. Results were compared by Student's t test. P < IIe -.<

6 270 ANTICARRIER ANTIBODY HOMEOSTATIC FUNCTION DISCUSSION The man fndng of the present study s the sustaned suppressve effect of passve IgG1 antcarrer antbodes on the actve IgG1 anthapten response, as opposed to the delayed enhancng effect of passve IgG1 anthapten antbodes. Beng avalable n purfed form and of comparable relatve avdty, IgG1 and IgG2 ant-hgg antbodes were used as antcarrer antbodes, snce they are drected aganst a restrcted number of determnants of the carrer moety of the DNP-BGG molecule. Theoretcally, the deal system would be to use two dfferent haptens, each one beng carrer for the other; but ths n the gunea pg does not allow delayed hypersenstvty (DH) to be studed. Furthermore, haptens do not seem to functon as carrers n ths speces (13). They may do so n the mouse (14), and ths would not be surprsng f haptens nduce DH n the mouse as they do n the rat (15; T. Neveu, unpublshed observatons). Indeed, the use of complete Freund's adjuvant for senstzaton n the studes on the carrer effect nduces DH to the carrer (13, 16, 17). Carrer and hapten determnants are unrelated, separate determnants (14, 17); ths concluson s strongly favored by experments where tolerance to the carrer reduces the response to the hapten (13, 18, 19). Carrer and hapten determnants must be on the same molecule (14, 17, 20), although recent reports challenge ths concluson (21-24). Nonetheless all reports suggest that two separate populatons of cells cooperate, antcarrer thymus-derved T cells and anthapten non-thymus-derved B cells. How these two populatons cooperate s not yet settled. In order to be actvated, the B cell apparently needs more than one sgnal: two or more molecules of antgen cross-lnked by antcarrer antbody (25) or by antcarrer T cells, these beng then lnked to the B cell through the antgen (26). In some nstances, however, the second sgnal does not orgnate n the antgen under study; T cells mght act on B cells ether drectly as n the allogenec effect (22, 23) or through the lberaton of a medator nduced by ther nteracton wth any antgen to whch they are senstzed (21, 24). These nterpretatons must be accepted wth cauton, nasmuch as they are nferred from complex systems n whch cross-reactvty between antgens mght furthermore exst. Ths, for example, seems to be the case of sheep RBC and horse RBC (27), the system used by Hartmann (21). Fnally, the recent report of Gershon and Kondo, whch suggests that T cells mght produce a "shut off" substance (28), makes any current nterpretaton even more dffcult. On the other hand, a cooperatng role of antcarrer antbody appears to be nvaldated by several experments (16, 17, 29). When gven passvely, antcarrer antbodes ether have no effect (6, 29) or yeld a consderable depresson of the anthapten response (16, 30). Ths has been our experence n the present study. Yet the IgG1 anthapten response was normal after passve IgG2 antcarrer antbodes and depressed

7 PHILIPPE VUAGNAT, THERESE NEVEU, GUY ANDRE VOISIN 271 after passve IgG1 antcarrer antbodes. Ths apparent dscrepancy could not be accounted for by a dfference n the dssocaton rate of these two antbody classes from mmune complexes. The nterpretaton we favor at ths tme s the followng: Antbody would nfluence antgen localzaton through ts class and then, at least for IgG1 antbodes, nfluence the mmune system accordng to ts specfcty, ether anthapten or antcarrer. Many observatons substantate these assumptons. Gunea pg IgG2 antbodes are cytophlc for macrophages and the strength of the bndng s consderably ncreased when the antbody has reacted wth the antgen (31). Smlarly, mouse B cells have a receptor exhbtng a marked predlecton for lgg1 antbody, the bond beng stablzed when the antbody has reacted wth the antgen (32, 33). Furthermore, only IgG1 antbodes have been shown to be hghly thymus dependent n the mouse (34, 35). There are many smlartes between mouse and gunea pg IgG1 antbodes, such as the trggerng of passve cutaneous anaphylaxs (36, 37); these smlartes justfy the assumpton that gunea pg IgG1 antbodes are thymus dependent too. Immunzaton wth IgG2-antgen complexes wll lead to antgen removal by the macrophages. Our observaton that antcarrer IgG2 antbodes were less suppressve than anthapten IgG2 antbodes may be explaned by the fact that only part of the few avalable determnants of our hghly hapten-substtuted carrer proten could combne wth the cross-reactng antcarrer antbodes we used. Immunzaton wth IgGl-antgen complexes, on the other hand, wll promote the persstence of the antgen n the mmune centers. Anthapten IgG1 antbody wll mask the haptenc determnants, but at the same tme wll allow senstzaton to the carrer, as suggested by Tada and Okumura (38). Ths, together wth the thymc dependency of IgG1 antbodes, would account for the brsk ncrease of anthapten IgG1 antbodes when the antgen s rentroduced. As for antcarrer IgG1 antbodes, they would shut off carrer-specfc T cells, ths resultng n a depressed anthapten antbody response, even after remmunzaton, as can be notced for the IgG1 response. Ths nterpretaton, akn to the "trpartte nactvaton model" proposed by Snclar et al. (39), gves a regulatory functon to IgG1 antbodes, as suggested by Crowle and Hu (40), and further reconcles the two man alternatves, perpheral vs. central, whch have been put forward to explan the role of antbody n the regulaton of the mmune response (41). It wll doubtless requre modfcaton as new evdence comes to lght, but t would seem for the present to be a convenent summary of sgnfcant nformaton. Such a scheme at least emphaszes the delcate balance and the dynamc ntrcaces between avalable commtted cells, antgenc determnants, and antbodes of the dfferent classes at any tme durng the mmune response.

8 272 ANTICARRIER ANTIBODY HOMEOSTATIC FUNCTION SUMMARY The effect of passvely admnstered IgG1 and IgG2 antcarrer antbodes on the IgG1 and IgG2 anthapten response has been studed. Gunea pgs were mmunzed wth dntrophenylated bovne gamma globuln mxed wth purfed IgG1 or IgG2 anthuman gamma globuln antbodes,.e., antbodes drected aganst a lmted range of the carrer determnants. Humoral IgG1 and IgG2 ant-dnp antbody contents were assayed at weekly ntervals and 4 to 10 days after a booster njecton of antgen n salne gven on the 12th wk. The man fndng was the sustaned suppressve effect of passve IgG1 antcarrer antbodes on the actve IgG1 anthapten response. Ths result s compared wth the enhancng effect of passve IgG1 anthapten antbodes and s dscussed n the lght of T cell-b cell and hapten-carrer relatonshps, leadng to the proposal of a regulatory functon of the Fc porton of the IgG1 antcarrer antbody, combned wth the antgen, on the T cell. We wsh to thank Dr. R. Bnagh for many helpful dscussons and Dr. Reu for makng avalable hs computng facltes. We also thank Mrs. M. Hoffmann and Mss P. Barreau for ther techncal assstance, Mrs. A. Voux for typng the manuscrpts, and Mr. J. Greller fol the llustratons. REFERENCES 1, Asherson, G. L., and S. H. Stone Selectve and specfc nhbton of 24-hour skn reactons n the gunea pg. I. Immune devaton: descrpton of the phenomenon and the effect of splenectomy. Immunology. 9: Dvorak, H. F., J. B. Bllote, J. S. McCarty, and M. H. Flax Immunologc unresponsveness n the adult gunea pg. III. Varaton of the antgen and vehcle of suppresson. Inducton of unresponsveness n the adult rat. J. Immunol. 97: Crowle, A. J., and C. C. Hu Specfcty of nhbton by antserum of the development o[ mmedate and delayed hypersenstvtes n mce. Proc. Soc. Exp. Bol. Med. 127: Vosn, G. A Immmfty and tolerance: a unfed concept. Cell. Immunol. 2: Playfar, J. H. L Cell cooperaton n the mmune response. Cln. Exp. Immunol. 8: Benacerraf, B., and P. G. H. Gell Studes on hypersenstvty. I. Delayed and Artbus-type skn reactvty to proten conjugates n gunea pgs. Immunology. 2: Esen, H. N Preparaton of purfed ant-2,4 dntrophenyl antbodes. Methods Med. Res. 10: Bnagh, R. A Producton of 7S mmunoglobulns n mmunzed gunea pgs. J. Immunol. 97:159. (b Avrameas, S., and T. Ternynck The cross-lnkng of protens wth glutaraldehyde and ts use for the preparaton of mmunoabsorbents, hnmunochemstry. 6:53.

9 PHILIPPE VUAGNAT, THJ~RESE NEVEU, GUY ANDR~ VOISIN Cerottn, J. C., P. J. McConahey, and F. J. Dxon The mmunosuppressve effect of passvely admnstered antbody IgG fragments. J. Immunol. 109.: McConahey, P. J., and F. J. Dxon A method of trace odnaton of protens for mmunologc studes. Int. Arch. Allergy Appl. Immunol. 9.9: Jandl, J. H., and R. L. Smmons The agglutnaton and senstzaton of red cells by metallc catons: nteractons between multvalent metals and the redcell membrane. Br. J. Haematol. 3: Paul, W. E., D. H. Katz, E. A. Godl, and B. Benacerraf Carrer functon n ant-hapten mmune responses. II. Specfc propertes of carrer cells capable of enhancng ant-hapten antbody responses. J. Exp. Med. 132: Mtchson, N. A., K. Rajewsky, and R. B. Taylor Cooperaton of antgenc determnants and of cells n the nducton of antbodes. In Developmental Aspects of Antbody Formaton and Structure. J. Sterzl and H. Rha, edtors. Publshng House of the Czechoslovak Academy of Scences, Praha Krtger, J., J. s. Wayland, and B. H. Waksman Specfcty of delayed responses to hapten-proten conjugates n rats. Immunochemstry. 8: Katz, D. H., W. E. Paul, E. A. Godl, and B. Benacerraf Carrer functon n ant-hapten mmune responses. I. Enhancement of prmary and secondary ant-hapten antbody responses by carrer premmunzaton. J. Exp. Med. 132: Rajewsky, K., V. Schrrmarcher, S. Nase, and N. K. Jerne The requrement of more than one antgenc determnant for mmunogencty. J. Exp. Med. 129: Rajewsky, K., and E. Rottl~nder Tolerance specfcty and the mmune response to lactc dehydrogenase soenzymes. Cold Sprng Harbor Syrup. Quant. Bol. 32: Benacerraf, B., I. Green, and W. E. Paul The mmune response of gunea pgs to hapten-poly-l-lysne conjugates as an example of the genetc control of the recognton of antgencty. Cold Sprng Harbor S~mp. Quant. Bol. 32: McBrde, R. A., and L. W. Schermann Hapten-carrer relatonshps of soantgens. A model for mmunologcal maturaton based on the converson of haptens to carrers by antbody. J. Exp. Med. 131: Hartmann, K.-U Inducton of a hemolysn response n vtro. Interacton of cells of bone marrow orgn and thymc orgn. J. Exp. Med. 132: Katz, D. H., W. E. Paul, E. A. Godl, and B. Benacerraf Carrer functon n ant-hapten antbody responses. III. Stmulaton of antbody synthess and facltaton of hapten-specfc secondary antbody responses by graft-versu,~host reactons. J. Exp. Med. 133: Kreth, H. W., and A. R. Wllamson Cell survellance model for lymphocyte cooperaton. Nature (Lond.). 234: Mallard, J., and B. R. Bloom Immunologcal adjuvants and the mechansm of cell cooperaton. J. Exp. Med. 136: Bretscher, P., and M. Cohn A theory of self-nonself dscrmnaton. Scence (Wash. D.C.). 169: Mtchson, N. A Cell populatons nvolved n mmune responses. In Ira-

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