NK cells, anti-tumor surveillance and interleukins

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(rostrum ) N K cells, anti-tumor surveillance and interleukins Osias Stutman Cellular Immunobiology Section, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, U.S.A. A class of cytotoxic effector cells found in normal and T-cell deficient mice can kill a variety of t u m o r and non-tumor target cells ~,-'. These effector cells a p p e a r in normal individuals without deliberate prior immunization and their existence, before its public acceptance, represented a major obstacle to the detection of specific a n t i - t u m o r cell-mediated i m m u n i t y 3-7. Some of the efforts to cope with such an unexpected nuisance are quite didactic, a n d range from the simple elimination of the incriminating normal controls to a reluctant description of the normal reactivity -~-7. Even in a 'citation classic' comment, it is stated that the authors would have felt ' h a p p i e r ' if they had realized in 1971 that what was attributed t o cell-mediated t u m o r i m m u n i t y i n c l u d e d o t h e r m e c h a n i s m s v. However, since a r o u n d 1975, the study of natural cellm e d i a t e d cytotoxicity ( N C M C ) has become a respectable endeavour, and even institutions entrenched in classical immunology have held workshops on the subject s . N C M C effector cells have some unique properties: high levels in the absence of priming, no immunological memory, polyclonality, lack of M H C restriction, undefined lineage and still undefined recognition events 2. These marked N C M C of either the natural killer (NK) ~ type or other related types (natural cytotoxic, NC; anomalous killer, AK; etc.) -~,') ~4 as a form of immune reactivity less conventional than T-cell- or even m a c r o p h a g e - m e d i a t e d cytotoxicity -~,*~. Although the N K effector cells have been most extensively studied in both mice and h u m a n s 2, it has become a p p a r e n t that the N C M C system is heterogeneous and contains a variety of closely related but discrete subclasses of effector cells 29 % Thus, the restriction of the definition of N C M C to the activity of prototype cells killing a few targets (i.e. YAC-I for murine NK cells and K-562 for the h u m a n counterpart), produced on the one hand a substantial amount of information concerning such cells and on the other, ideas about heterogeneity based on the discrepancies between 'classical' N K cells and ' o t h e r ' effectors of N C M C e,,~ 14.1,, J~ However, regardless of the attributes and mechanics of the

N C M C system, a c o m m o n set of goals for most investigators in the field has been: (1) to define the function of the system zr~ viv0, especi~illy as a possible a n t i t u m o r surveillance device; and (2) to put the system in some perspective in relation to more conventional T - B - m a c r o p h a g e immunology. The contents of two recent articles of different quality have been hailed as a fulfilment of these expectations. The first paper, discussing some surface properties of the effectors, ~9 suggests that N K cells may have an a n t i - t u m o r effect in vivo. The second 2° shows that interleukin-2 (IL-2), a factor which plays an important role in T-cell growth and function, also affects N K activity. Thus, the first p a p e r belongs to the group of publications which attempts to settle the in-vivo effect v. in-vilro artifact argument while the second p a p e r pleases the immunologists (at least in the opinion of the ./Val~re epigone 2~), since it brings N K cells ' f i r m l y . . . within the fraternal order of the true immunological n e t w o r k s . . , irrespective of the details of the mechanisms of the interleukin-2 effect...'2~. However, both papers (as well as the c o m m e n t a r y ) present some problems of interpretation, especially the study on possible effects in vivo ~9. In the first paper, Kasai e! aP '~ show that the in-vivo administration of a xenogeneic antibody against the cell surface ganglioside asialo-GM1 produced a reduction of N K activity when tested in vilro against YAC-1 targets and resulted in a higher incidence of takes of the R L d l lymphoma, syngeneic for the B A L B / c nude hosts. Both the authors as well as the ,/Valure comm e n t a t o r agree that the a n t i b o d y is 'blocking N K activity '2~ and that the increase in t u m o r takes is the consequence of such blocking. The presence of asialoG M I on N K cells is well documented 17,1~,22-24. However, some of the conclusions about the effects of the anti-asialo-GM1 in e,,i~o can be questioned, since other interpretations m a y be more pertinent. There is an a p p a r e n t lack of a p p r o p r i a t e controls for the in-vivo treatment, such as another rabbit anti-mouse reagent instead of normal serum: active N K ~,25 and related invivo p h e n o m e n a such as resistance to hemopoietic Elscvier/Noilh-Holland Biunlcdical Press 1981 0167 - 4919/81/0(J00

01)(ffl/$2.7~

206 grafting 25 are quite susceptible to inhibition by antimouse species xeno-antisera. Besides this it is surprising that the authors did not cite their own findings showing that aslalo-GM1 is a/so present on the tumors ' used for the study (YAC-1 an d RL <~1) >, . It is obvious that the in-e,ieJo effects of an a n t i b o d y directed to antigens present on both the putative effector cells (NK) and the tumor under study require a more complex interpretation than the blocking of N K activity proposed, interpretations which may range from the 'old fashioned' enhancement of t u m o r growth 27, to modulation of surface structures on the target 2~, or any other of the complex in-edvo eflects of passive a n t i b o d y 2v, which may or m a y not include actual effects on the N K effector cells. N K cells are touched by the recent surge of interest in interferon 5°, since interferon has been shown to augment N C M C activity, especially of the N K type 2,24,31. The second paper, by Henney el al. 2°, shows that IL-2 can also augment N K activity a n d even has an additive effect when combined with interferon. Facing the possible criticism that crude supernatants of spleen cells incubated with con A or P H A contain many other things besides IL-2, such as interferon or hemopoietic colony stimulating factors 5>35, Henney el al. showed that reasonably pure preparations of IL-2 produced effects c o m p a r a b l e with those of less pure preparations and that a monoclonal a n t i b o d y against IL-2 reduced the IL-2-induced augmentation of N K activity 2°. T h e .Nah~re c o m m e n t a r y 2~ indicates that ' . . . it is not surprising that NK regulation has now been shown to depend on signals other than interferon . . . , ' a statement with which it is easy to agree 2. However, two comments can be made on the effects of IL-2: (1) it is becoming a p p a r e n t that functions attributable to IL-2 may be related to other active lymphokines or monokines in the supernatants, and that we may be faced with IL-3, 4, etc. in the near future32.33; a n d (2) based on the units of 1L-2 used by Henney el a[2°, it appears that NK activation may be a relatively ' h i g h ' dose event, somewhat insensitive to less than 0.5 units, since in one experiment with the monoclonal anti-IL-2, the remaining 0.2 or 0.4 units after a n t i b o d y treatment (which are amounts quite active in other systems3<3<'), had no effect on N K activity, while the original preparations containing 1.5-3.8 units were effective; whether this indicates that the IL-2 effccts are indirect is certainly an open question. Quite wisely, Henney and his colleagues 2° do not speculate beyond the factual description of their results, but suggest that the potentiating effects of interferon on N K activity m a y be due to IL-2, a view also shared by the ,Nature c o m m e n t a t o r 2~, but which is not directly supported by the N K - a u g m e n t i n g effects of pure interferons 2,2<3.. However, both the factors regulating the production of interferons 3~ or IL-232,33, as welt as the cellular or humoral regulation of N C M C

immunology loday, Novelnber 1981

activity 2,3v are still poorly defined, making the argument just a matter of opinion. Interestingly, the 'long' version of both papers 3s,39 a p p e a r e d almost simultaneously with the ' s h o r t ' versions 19,2°. In the case of the asialo-GM1 studies, the longer version does not clarify the issues I have discussed: normal rabbit serum is the only control and the discussion of studies with mouse tumors in vivo using, both YAC-1 and RLc~ makes no mention that the asialo-GM1 determinant is also on the target cells 38. In addition they show results with two h u m a n tumors, a ' T cell l y m p h o m a / l e u k e m i a ' and a gastric carcinoma. T r e a t m e n t of nude mice with asialo-GM1 strikingly increased the t u m o r size and incidence of tumor takes, especially of the T l y m p h o m a 35, with only marginal effects on the gastric tumor. Since the authors also showed that asialo-GM1 is a surface marker for h u m a n acute lymphoblastic leukemia 4°, it would have been useful to know if the ' T l y m p h o m a ' used also expresse d the marker. Unfortunately this is not discussed. In the long version of the IL-2 paper, 3') although the argument concerning IL-2 a m o u n t s still holds (as shown by T a b l e III in the paper) some interesting new findings are reported: (1) interferon-activated cells with N K characteristics can be grown for long periods of time in the presence of IL-21s.w; and (2) it is possible that interferon or interferon inducers may act by favoring IL-2 absorption by cells, i.e. by increasing IL-2 receptors on T as well as N K cells 39. This is indeed an attractive and testable interpretation of the effects of II,-2 on NK activity and represents a true addition to the short papcr. During our studies of oncogenesis in nude mice <, we indicated that thymus-deficient mice may well be useful models for the study of alternate pathways for the development of cell-mediated cytotoxic mechanisms, of which N C M C may be the prime example. The lineage of N C M C is still undefined 2 but our views were recently expanded 24 to the proposition that if N K cells have antigen-specific recognition (or in fact any form of recognition, such as the lectin-like receptors reactive with an a p p r o p r i a t e concentration or display of surface sugars on the targets we studied<~2), N C M C might represent an extra-thymic alternative p a t h w a y for the production of cyt0toxic cells which are not M H C restricted 24, whatever their lineage. Perhaps it may act as part of a more 'primitive '42 recognition systcm, capable of handling a variety of viruses, parasites, infected cells, some normal hemopoietic cells and tumors *s. Discussing the results of Henney e! aL >, the .¥alure c o m m e n t a t o r questions whether the function of N K cells ' . . . n e e d necessarily be the killing of tumor cells.' This is indeed an i m p o r t a n t point. As we have repeatedly insisted in the past years during our analysis of the concept of immunological surveillance against tumors 43 4s, from an evolutionary

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s t a n d p o i n t there is no a p p a r e n t need for a defense m e c h a n i s m against t u m o r d e v e l o p m e n t , no m a t t e r how desirable such a m e c h a n i s m m a y be, since malign a n c y certainly does not represent a t h r e a t to the species. ( F r o m the ' c r e a t i o n i s t ' s t a n d p o i n t , w h i c h d e m a n d s equal time, there is also no n e e d for such a defense m e c h a n i s m , since it represents j u s t a n o t h e r e x a m p l e of the p r e d a t o r - p r e y t h e m e in its simplest t e r m s ; regrettably I have not the space to e x p a n d on this variant). Leslie Brent soberly suggested in 195840 that the h o m o g r a f t r e a c t i o n ' . . . m a y be r e g a r d e d as the price paid for an efficient system of defence against bacterial and viral i n v a s i o n . . . ', the ' p r i c e p a i d ' being the obstacle it presents to o r g a n t r a n s p l a n t a t i o n . In the case of the possible a n t i - t u m o r effects of N C M C , one m a y say, p a r a p h r a s i n g Brent, that it is the benefit o b t a i n e d from having a system that c a n react rapidly against foreign invaders or u n w a n t e d differentiation 45. D u r i n g our criticism of the ideas s u r r o u n d i n g immunological surveillance and its thymusdependence4~ 45, I i n d i c a t e d that one of the conseq u e n c e s of strongly a u t h o r i t a r i a n a n d a t t r a c t i v e h y p o t h e s e s was the d e v e l o p m e n t of a r a p i d l y m o v i n g field w h i c h p r o d u c e d poor q u a l i t y p u b l i s h e d r e s e a r c h ( p r o v i d e d that it s u p p o r t e d the t h e o r y or the t r e n d ) and an a b u n d a n c e of reviews a n d s y m p o s i a by invitation, with their o b l i g a t o r y p a p e r s p u b l i s h e d w i t h i n a book. U n d e r these conditions, the review articles usually c o n t a i n half-digested c o n c e p t s a n d results w h i c h are p r e s e n t e d in an i n c o h e r e n t form, p r o d u c i n g c o n c e p t u a l confusion and d o g m a t i s m (see Ref. 43 for m o r e details). It seems that the s a m e s i t u a t i o n applies to the field of N C M C in g e n e r a l and to t h e N K a r e a in p a r t i c u l a r . In a review on N C M C 47 (no one is totally free of them), I w r o t e that ~agreement a n d d i s s e n t ' d o m i n a t e the views of the general c h a r a c t e r i s t i c s of N C M C effector cells and i n d i c a t e d t h a t one of the reasons for the d i s a g r e e m e n t was that several 'facts' c o n c e r n i n g N K cells had ' . . . r e a c h e d the levels of a c c e p t e d truths, especially after b e i n g i n c l u d e d in review articles. '47 T h r o u g h this p r o c e d u r e , m a n y of these facts have b e c o m e established by simple repetition as ' . . . some a b s o l u t e p r o p e r t y of the N K c e l I . . . ' , a p r o p e r t y which after ' . . . further study a p p e a r s to be q u i t e variable. ,47 In m y view the two p a p e r s discussed ( p e r h a p s four, if the ' l o n g ' versions are c o n s i d e r e d ) s u p p o r t m y c l a i m that d u r i n g periods of active g r o w t h of an area, p u b l i c a t i o n s of u n e v e n q u a l i t y are p r o d u c e d . H o w e v e r , it is also a p p a r e n t that, while the p h e n o m e n a are there, as seems to be the case for the a s i a t o - G M l studies discussed "~,3s, the i n t e r p r e t a t i o n s of the findings are the q u e s t i o n a b l e points, a n d future c o m m e n t a r i e s may, I hope, re-interpret the N K schemes. I h a v e played here the role of i m m u n o l o g i c a l p u n d i t on N K cells but in areas that are in such r a p i d flux, it is r e a s o n a b l y safe to give opinions, even critical ones.

H o w e v e r , as A l e x a n d e r Pope indicated, ' . . . the v u l g a r boil, the l e a r n e d roast an egg . . . ' % a n d o v e r - r o a s t i n g is indeed one of the d a n g e r s in these types of c o m m e n t a r i e s , especially since it is '. , . h a r d to hit the p a l a t e of such g u e s t s . . . ' 4 s .

References 1 Kiessling, R., Klein, E. and Wigzell, H. (I975)E,r.ff. Immunot. 5,112-117 2 Herberman, R. B. (ed.) (1980).¥?llnral C~l/-me&aled hnnum~t~ Againsl Tnmors Academic Press, New York 3 Takasugi, M., Mickey, M. R. and Terasaki, P. I. (1973) CTmcer Res. 33, 2898 2902 4 Conference and Workshop on Cellular Immune Reactions to Human Tumor Associated Antigens, (1973) Natl. Cancer lnrt. Monogr. No..37

5 Bean, M. A., Bloom, R. B., tlerberman, R. B., Old, L. J., Oettgen, H. F., Klein, G. and Terry, W. I). (1975) Camer Res. 35, 2902-2913 6 Bloom, B. R: and David, ,J. R. eds. (1976) In Vilro ,~[elkodt in Ce[l-medinld and T , mor hmnunio,, Academic Press, New York 7 Hellstrom, I. and Hellstrom, K. E. (1981) O~rr. Conic,Is (Li/} Sci.) 24, 14 8 Langman, R. (1980) .VaDer¢(London) 286, 208 9 Stutman, O., Paige, C. J. and Feo Figarella, E. (1978)J. Immmmt. I21 1819-1826 10 Karre, K. and Seeley, J. K. (1979), 7. Imm,rml. 12~, 1511-1518 1/ Kumar, V., l~uevano, E. and Bennett, M. (1979), 7 . l£vp. Med. 150, 531-547 12 Burton, R. C. (1980) in .Va/nra/ Cell-Medialed bnmtmi(y Agaim! Tnmorr, (Herberman, R. B., ed.)pp. 19-35, Academic Press, New York 13 Welsh, Jr., R. M., Zinkernagel, R. M. and tlaIlenbek, L. A. (t979) ft. bmnnnot. 122, 475-481 14 Tai, A., Burton, R. C. and Warner, N. l.. 11980).7- lmm,rml. 124, 1705-1711 15 Cudkowicz, G., Landy, M. and Shearer, G. M. (eds.) 11978) .~Val,ra/ Res~.~lntue @,rictus agamsf P)m'(gn (,~lh, Tmnors and Micro&s Academic Press, New York

t6 Paige, C. J., Fro Figarella, E., Cuttito, M..J., Cahan, A. and Stutman, O. (1978). 7. bnmnnol. 12t, 1827-1835 17 Lattime, E. C., Pecoraro. G. A. and Stutman, O. 1198t)ft. b~mmno[. 126, 2011-2014 I8 l)ennert, (,., Yogeeswaran, G. and Yamagata, S. (t981).7. Exp. Ale& 153, 545-556 19 Kasai, M., Yoneda, T., llabu, S., Maruyama, Y., Okumura, K. and Tokunaga, T. ( 198 t ) ,'~T~h*re(L,ndon) 291,334-335 21) Henney, C. S., Kuribayashi, K., Kern, 1). E. and Gillis, S. ( 1981)Vah¢re ( Lmuk,n) 29 [, 335-338 21 Beverly, P, (I981) ,%dnr¢(Lomhm) 291,288 22 Kasai, M., lwamori, hi., Nagai, Y., Okumura, K. and Tada, T. (1980) Eitr..7" Immn*m[. 111, [ 75-180 23 Young, W. W., Hakomori, S. 1., l)urdik, J. M. and Henney, C. S. (1980), 7. Innnnnog. 124, 199-201 24 Minato, N., Reid, L., Cantor, H., Lcngyel, P. and Bloom, R. B. (1980)J. l~x/>..lied. 152, 124-137 25 Cudkowicz, G. (1978) in ,'vSdnrag Re.,trlance ,~)'.rtems Awinst Fc>re~qm(,?[l.~, Tnm,r.~. and M~}r¢,he~ (Cudkowicz, G. l.andy, M. and Shearer, B. M., eds) pp. 3-~ L, Academic Press, New York 26 [tabu, S., Kasai, M., Nagai, Y., Tamaoki, N., Tada, T., Herzenberg, L. A. and ()kumura, K. (1980).7- bmnnnoL 125, 2284-2288 27 Kaliss, N. (1958) (.?m,,t Re,. 18, 992-1003 28 Old, L. ,I., Stockert, E., Boyse, E. A. and Kim, .]. H. 11968}.7. t'~vp. Mrd. 127,523-539 29 Moller, G. (ed.)(1975) 7?an~7/anhttion nn'., 27

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30 Bloom, P,. B. (198(/).Vblnre(Lmzdon)284, 593 595 31 Vilcek, ,j., Gresser, I. and Merigan, T. C. (eds). (1980) Arm. ,,V. K Acad. Sci. VoI. 350 32 Behring [n.~L Mill (1980) Vol. 67 33 Moller, G. (ed.) (1980) [ram,no~. Rer. 51 34 Gillis, S., Ferm, M. M. Ou, W. and Smith, K. A. (1978)ft. lmm,noL 120, 2027-2032 35 Gillis, S. and Stul], D. (1981)J. lmm,noA 126, 1680-1683 36 Lattime, E. C., Gillis, S., David, C. and Stutman, O. (1981) E,r. ft. lmnmrm/. I1, 67-69 37 Cudkowicz, G. and Hochman, P. S. (1979) Immano/. Rev. 44, 13-41 38 Habu, S., Fukui, H., Shimamura, K., Kasai, bel., Nagai, Y., Okum.ura, K. and Tamaoki, N. (I981)ft. Imm,no[. 127, 34-38 39 Kuribayashi, K., Gillis, S., Kern, 1). E. and tIenney, C. S. ( 1981) J. lmmuno/, 126, 2321-2327 40 Nakahara, K., Ohashi, T., Oda, T., Hirano, T., Kasai, M.,

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OkumuPa, K. and Tada, T. (1980) .'Vi Eng/. ,7' Med. 302, 674-677

41 Stutman, O. (1975) ,7. Iron,rod. 114, 1213-1217 42 Stutman, O., l)ien, P., Wisun, R. and Lattime E. C. (1980) .P~o(-..V?d[.Arad. Sol. [/,%'A.77, 2895-2898 43 Stutman, O. (1975) Adv. Cancer Re~. 22, 261-422 44 Stutman, O. (1977) in Oriioin, q/ lluman Gancer (Hiatt, II. H., Watson, H. D. and Winsten, J. A., eds) pp. 729-750, Cold Spring Harbor Laboratories, New York 45 Stutman, O. (1981) in Tt,, ttandho(M qf Cancer Imm,no/ogy, ~'ol. 7 (H. Waters, ed.) pp. 1-25, Garland STPM Press, New York 46 Brent, L. (1958) t'rog..4/le~W 5, 271-348 47 Stutman, O., Feo Figarella, E., Paige, C. ,j. and Lattime, E. C. (1980) in ,'Val,ral Cell-31edmled lmm,nitl, ,4~Tain.~l T~Lmorr (Herberman, R. B., ed.) pp. 187-229, Academic Press, New York 48 7"ke (,'on~plete Poeh(al ,[t'cJrX.~qf ,llevl;nder Pope (1903) p. 198, Houghton Milttin Co., Boston

1 Anti-MHC antibody idiotypes as important elements in immunoregulation

ldiotypes (Ids) are defined as antigenic d e t e r m i n a n t s on the variable regions of a n t i b o d y molecules. T w o types of Id are d i s t i n g u i s h e d - those which are related to a n a n t i g e n - c o m b i n i n g site a n d those which are not (framework ids) ~. T h e a n t i - I d a n t i b o d y response in rive is t h y m u s - d e p e n d e n t 23, i.e. specific T cells are involved. If a n a n t i - I d a n t i b o d y response is elicited in a xenogeneic host helper T cells (Tu) could recognize Id, allotypes a n d isotypes but in syngeneic or allogeneic c o m b i n a t i o n s , T H cells are limited to the recognition of Id a n d I d / a l l o t y p e s , respectively 4,5. G e n e r a l l y x e n o - i m m u n i z a t i o n favours the p r o d u c t i o n of a n t i b o d i e s specific for framework ld, whereas syngeneic or allogencic i m m u n i z a t i o n favours the p r o d u c tion of a n t i b o d i e s recognizing c o m b i n i n g - s i t e related Id, t h o u g h this is not a strict rule. T h e most recent theories c o n c e r n i n g T - B cell c o l l a b o r a t i o n in the specific a n t i b o d y response to a n t i g e n state that two types o f t H cells are at play: (1) antigen-specific, s e l f - M H C restricted T u cells a n d (2) a n t i - l d , n o n - M H C restricted T u cells. A c c o r d i n g to such theories Ir-gene effects are expressed via the first type of helper cells". T h e r e are i n d i c a t i o n s in the literature that the a n t i - I d a n t i b o d y response is also regulated by lr-genes >. In p a r t i c u l a r M t IC-restricted, Id-specific TH cells a n d a n t i - ( a n t i - l d ) specific, n o n M H C restricted T u cells m a y regulate the syngeneic a n t i - I d a n t i b o d y response. it has long b e e n k n o w n that the injection of specific a n t i b o d y before, together with, or ,just after a n t i g e n could either i n h i b i t or e n h a n c e the specific a n t i b o d y ~, Elxcxicr/Nol'lh H o l l a n d Bionu'dic;l[ Press 1981 [1167 - 1919/8 l/f)[)O0 - 0 0 0 0 / $ 2 7 5

response 7. A n t i - I d a n t i b o d i e s c a n also either a u g m e n t or suppress the Id response in e x p e r i m e n t a l a n i m a l s subsequently injected with specific a n t i g e n s& M o n o c l o n a l a n t i b o d i e s have b e e n p r o d u c e d against different d e t e r m i n a n t s of the I1-2 c o m p l e x in the mouse, i.e. H-2 K, D or I region d e t e r m i n a n t s ~°,~,j2. Because these d e t e r m i n a n t s or the whole molecules b e a r i n g these d e t e r m i n a n t s arc involved in specific i m m u n e reactions, a l l o a n t i g e n r e c o g n i t i o n a n d Ir-gene effects L~, the i m p o r t a n c e of Ids on a n t i - H - 2 a n t i b o d i e s a n d their interaction with a n t i - I d a n t i b o d i e s has attracted m u c h interest d u r i n g the last years. In 1974, M c K e a r n a n d colleagues showed that the a n t i b o d y response towards a l l o a n t i g e n was regulated by a n t i - I d antibodies~L These studies were extended a n d explored extensively by Ramseier, L i n d e n m a n n , Binz a n d WigzelI a n d colleagues. A m o n g their findings was the d e m o n s t r a t i o n that ir~jection of a n t i b o d i e s to Id located on a n t i b o d i e s to AgB locus d e t e r m i n a n t s (the M H C in the rat) elicited a specific anti-AgB a n t i b o d y response that was significantly higher t h a n that s t i m u l a t e d by injection of A g g a l l o a n t i g e n I Q Now Sachs a n d c o l l e a g u e s have reported ~' that xenogencic a n t i - l d a n t i b o d i e s against mouse m o n o c l o n a l a n t i - H - 2 K k a n t i b o d i e s can i n d u c e the synthesis of I d - b e a r i n g i m m u n o g l o b u l i n (Ig) molecules, some of which have a n t i - H - 2 K k a n t i b o d y activity. Pierres a n d colleagues have d e m o n s t r a t e d the same p h e n o m e n o n by injecting xenogeneic a n t i - I d antibodies against Id on a n t i - I A k or a n t i - I E k m A b iT. T h u s , it appears as if there are m a n y Ig molecules