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Immunology 7-o@, rot. 3, No. 2, 1982

References 1 Hewitt, H. B., Blake, E. R. and Walder, E. S. (1976) Br. J. Cancer 33, 241-259 2 Klein, G. and Klein, E. (1977) 7-ra>~i:)lan!Proc. 9, 1095-1104 3 Weiss, I). (1977) Cancerlmm~mot, lmmunolher. 2, 11 19 4 Kobayashi, H. (ed) (1979) Immunological xenogenizalion of tumor cell.~. GANN Monograph on Cancer Research No. 23, Japan Scientilic Societies Press, Tokyo 5 Prager, M. and Baechtel, F. S. (1973) Metho& Cancer Res. 9, 339-400 6 Boon, T. and Kellerman, O. (1977) P~oc.2¢ot[. Acad. Sci. U.S.A. 74, 272-277 7 Boon, T. and Van Pel, A. (1978) 15oc../Vatl. Acad. Sci. U.S.A. 75, 1519-1523 8 Van Pel, A., Gcorlette, M. and Boon, T. (1979) PToc..Natl. Acad. Sci. U.S.A. 76, 5282-5285 9 Uyttenhove, C., Van Snick, J. and Boon, T. (1980) J. Exp. Med. 152,1175 1183 10 Boon, T., Van Snick, J., Van Pel, A., Uyttenhove, C. and Marchand, M. (1980). 7. Exp. Med. 152, 1184-1193 11 Bonmassar, E., Bonmassar, A., Vadlamudi, S. and Goldin, A. (1970) Proc. )¢?~tl. Acad. Sci. U.S.A. 66, 1089-1093 12 Riecardi, C., Fioreni, C., Giampietri, A., Pucceni, P. and Goldin, A. (1978) Transplant. Proc. 25, 63 68

D] (,..,.-.

13 Giampietri, A., Fioretti, C., Goldin, A. and Bonmassar, E. (l 980)J. ]V?dl. Cancer Irnl. 64,297-301 14 Nicholin, A., Veronese, F., Marelli, O. and Goldin, A. (1980) Cancer lmmunol, lmmJmother. 9, 43-48 15 BrombergJ., Brenan, M., Clark, E. A., Lake, P., Mitchison, N. A., Nakashima, I. and Sainis, K. B. (1979) in Immunological xenogenizaZior~ of minor cells. GANN Monograph on Cancer Research No. 23, pp. 185-192Japan Scientific Societies Press, Tokyo 16 Tsukagoshi, S. and Hashimoto, Y. (1973) (,?racer Re.~. 33, 1938-2042 17 Bonmassar, E., Prada, G., Giannattasio, G. and Testorelli, C. (1965) Arch. ltat. Path. 8,231-237 18 Nicolin, A., Vadlamudi, S. and Goldin, A. (1972) Cancer Res. 32, 653-657 19 Kerbel, R. S. (1979) Am.J. Path. 97,609 622 20 Dennis, J. W., Donaghue, T. P., Carlow, D. A. and Kerbel, R. S. (1981) CancerRer. 41,4010-4019 21 Embleton, M. J. and Middle, J. G. (/981) Br. ,7. Cancer 43, 44-52 22 Kerbel, R. S. (1979)Nature (L(mdmT) 280, 358-360 23 Nowell, P. (1976) Science 14, 23-28 24 Fisher, M. S. and Cifore, M. A. (1981) Cancer Res. 41, 3018-3023

)

Accessory cells unrelated to mononuclear phagocytes and not of bone marrow origin Peter E. Lipsky and John R. Kettman l)epartments of Internal Medicine and Microbiology, UTHSC1) Southwestern Medical School, Dallas, T X 75235, U.S.A. The ind~lction and regTdalion o/ irrzmune re~])m~se~ require the participation of cells which maintain lymphocyte viability, promote ~ecesvary celhdar interaclio~s, secrete imm~moreguIatory molecules arid presen! antzgen. These are accesso O, eeltr, and their ,fimctio,~ i,r r~ot antigen-specific. Classical{y, celtr qf the monomtclear phagocyte lineage kae:e beer~ eon.ridered to be the major accessory ceil po/mlation in most z'mm~me re.~])on.res. More receT~t{y, olker cell t~/)e.r, .v~ek as Langerhans cells of the .rkin and &ndritie cells of Ike lyr~pkoid orgar~.r, have also been shown Io be e[/}'cti~:e. This argiele reviews the evidence that additional cell type.r, such a.r endothelial cells or.fibroblasts, serve an aecesso(y role in immune re.~;tm~lses. T h e g e n e r a t i o n a n d e x p r e s s i o n of i m m u n e res p o n s e s involves a c o m p l e x series of cellular intera c t i o n s b e t w e e n various l y m p h o c y t e s u b p o p u l a t i o n s , T h e h a l l m a r k of these events is specificity, b o t h in t h e r e s p o n s e to a n t i g e n reactivity a n d in t h e w a y l y m p h o eyte s u b s e t s interact. C l o n e s of reactive l y m p h o c y t e s r e m a i n w i t h i n the various l y m p h o i d o r g a n s or circulate in the blood in a r e s t i n g state until c h a l l e n g e b y a n t i g e n specifically initiates their activation. T h e result is a tightly r e g u l a t e d r e s p o n s e . A n t i g e n is t h u s a n e c e s s a r y signal tor specific i m m u n e r e s p o n s e s b u t in m o s t c i r c u m s t a n c e s a n t i g e n alone is not sufficient to trigger l y m p h o c y t e activation. T h e active particip a t i o n of a n o t h e r cell type t h a t lacks a n t i g e n specificity is also necessary. B e c a u s e it is not part of t h e Elsevier Biomedical Press 1')82

0167- 4919/82/00[)0-0(}0()/$2.75

antigcn-specific n e t w o r k of reaetiw: l y m p h o c y t e s it is t h o u g h t of as a n a c c e s s o r y cell. Before it was a p p r e c i a t e d t h a t the cellular i n t e r a c t i o n s involved in immune responses were under genetic control, accessory cells were t h o u g h t to have no restrictive properties a n d thereR)re to be c o m p l e t e l y non-specific. M o r e recently, it h a s b e c o m e a p p a r e n t t h a t the accessory, or a n t i g e n - p r e s e n t i n g cell, e x p r e s s e s gene p r o d u c t s of t h e m a j o r h i s t o c o m p a t i M l i t y c o m p l e x ( M H C ) t h a t limit a n t i g e n recognition. However, even in this c o n t e x t accessory cells r e m a i n ' n o n - s p e c i f i c ' in t h e sense that t h e y provide a c o n t e x t in w h i c h the specificity of a variety of different a n t i g e n i c determ i n a n t s c a n be displayed. T h i s review will detail the various f u n c t i o n s of a c c e s s o r y cells in the initiation of

Immunology Today, vol. 3, .N)~.2, 19~'~2

37

immune responses and will also examine some of the diverse cell types capable of accomplishing these varied functions. A c c e s s o r y function of cells of m o n o n u c l e a r p h a g o c y t e lineage Early studies with intact animals produced four lines of evidence that cells of the mononuclear phagocyte lineage played an essential role in the induction of i m m u n e responses ~. Firstly, administration of antigen to animals resulted in its [)referential uptake hy macrophages and other macrophage-like cells of lymphoid organs, where it tended to persist in immunogcnic form for prolonged periods of time. Secondly, the immunogenicity of an antigen was related to the extent to which it was ingested by a macrophage. Thirdly, depression of the endocytic capacity of macrophages by ' R E S blockade' tended to diminish the induction of immune responses. Finally, macrophages that had taken up small amounts of antigen in z~itro were able to induce both antibody production and delayed-type hypersensitivity upon transfer to a normal recipient. Moreover, macrop h a g e - b o u n d antigen appeared to be considerably more immunogenic t h a n free antigen. In several species, assays of accessory-cell function using a variety of irz-vilro correlates of immune responsiveness showed that macrophages were not only important but necessary for the initiation of immune responses 2. The experiments examined the effect on in-vitro responses of depleting macrophages from mixed cell populations. Depletion was by several techniques that exploited differences between macrophages and lymphocytcs, including adherence, size, density, phagocytosis and surface markers, lnterpretaLymphocyte DNA Synthesis

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