205
immunology to@, ,Nbvembe~ 1,981
(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 , . 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..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
208
imm~r*o/ogy l~)&O',3,)n'emher 1.()8I
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.,
133
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
immunology to@, ,Nbvembe~ 1,981
(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 , . 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..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
208
imm~r*o/ogy l~)&O',3,)n'emher 1.()8I
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.,
133
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
