The genetic control of immune responses

The genetic control of immune responses

149 immunoloW to&{y, Augu.rl 1981 The genetic control of immune responses Professor McDevitt began with a fascinating account of the events leading ...

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149

immunoloW to&{y, Augu.rl 1981

The genetic control of immune responses Professor McDevitt began with a fascinating account of the events leading up to the discovery of i m m u n e response genes. The well-defined synthetic antigen (T,G)-A--L (described in Professor Sela's talk) had elicited a good antibody response in Israeli rabbits but attempts to produce such antibodies in the rabbits at Mill Hill failed completely. After checks on the antigen it fell to McDevitt to solve the antibody production problem and it was family studies on the offspring of responder and non-responder rabbits which led to the discovery of i m m u n e response genes. However, this work was m u c h delayed because male rabbits given four foot-pad injections with complete Freund's adjuvant to ascertain their responder status to synthetic antigen all failed to respond to the female of the species. Having completely exhausted the Mill Hill rabbits the high and low responder story was followed in inbred mouse strains and it was the combination of clearly-defined antigenic determinants and clearly-defined mouse strains which led to the ultimate success of the immune-response gene investigations. Moving to the present McDevitt posed two questions: (1) what is the genetic origin of the I region?; (2) how do I-R genes function? T h e answer to both is: we do not know. At present at least 12 genes are known in the I region (Aa, Ab, Ae, TTH , Iaw39, Ir-nase, IJi-Ts, IJ2-TH, IJz-accessory cell, E, Ts for MLR, lr-myoglobin). In addition there can be more gene products because of the interactions of the c~ chains of one region with the 13 chains of another. Yet, despite the present deficiencies in our knowledge we can manipulate the i m m u n e response in vivo remarkably well. McDevitt chose examples based on animal models of diseases with an auto-immune involvement which followed on from the pioneering studies of Davies (anti-Ia will enhance grafts) and Benacerraf (anti I-J will modify the response to tumours and to sheep red cells). McDevitt's contribution, however, is in the use of antibody to remove the effect of the Ia region products of one haplotype and thus make the animal behave as if it has only the la region genes of the second haplotype. (A simple example is where help is given to a sailing boat by a high wind a n d suppression is supplied by an opposing current. Removal of the high wind leads to a very significant course alteration but it

is very difficult except in an ideal situation to predict how the remaining wind current and boat will interact.) In the example shown in Table I the H-2 b parental strain is a high rcsponder to (T,G)-A--L and a low responder to (H,G)-A-L, while the second parental strain H-2 k is exactly the opposite. The offspring may be low or high responders depending on the interactions of the haplotype gene products. However, giving the offspring antibody against H-2 k makes it behave as an H-2 b a n d vice versa. This answer is less specific if complete Freund's adjuvant is used with the (T,G)-A--L a n d (H,G)-A--L. Without adjuvant, however, the 'haplotype suppression' is observed specifically for both primary and secondary responses. Although not so clear cut as in the response to synthetic TABLE ! Genetic control and haplotype suppression H-2 genotype h K K/b (F,) /f/b (F2) K/b (F2)

Treatment

anti H-2 k anti H-2 t'

Response to (TG)-A-L. (HG)-A-L lfigh Low High High Low

Low High Low Low lligh

antigens, the use of haplotype suppression in the mouse model for experimental a u t o i m m u n e encephalomyelitis. By such suppression the incidence of clinical disease was reduced from 10/18 animals in the untreated to 1 / I 9 in a treated group. T h e possibility of using monoclonal antibodies for haplotype suppression in patients must be approached with caution, not least because the tissue distribution of Ia is different in man, including, tbr example, mesangial cells and oligodendritic cells. Mouse monoclonal antibodies against h u m a n T cell subsets have been used to treat p a t i e n t s w i t h o u t i n d u c i n g u n a c c e p t a b l e responses, although in this case the very cells which could induce such responses may have been inactivated by the antibody. II. O. McDevilt i~ al Stan/brd U~liver.rilySchool qf Medicine, Stanfi~rd, CA 94,305, U.S.A.

Cell interactions in specific immune suppression Regulation of immune responses involves a complex series of cell-cell interactions and cxtracellular signals which modulate the type and intensity of the response. Two sets of gene products are involved in such regulation, the products of lgH- 1 and I region genes. O u r laboratory has been concerned over the last few years with the basis of the suppression of delayed-type hypersensitivity ( D T H ) to the azobenzenearsonate determ i n a n t (ABA) in A / J mice which express the crossreactive idiotype (CRI) that characterizes the anti-ABA antibody response in this strain. Sensitization to ABA is obtained by subcutaneous immunization with ABA-conjugated syngeneic spleen cells

(ABA-SC), whereas ABA-specific suppressor T cells capable of suppressing the development of ABA D T H result from the intravenous administration of ABA-conjugated syngeneic spleen cells. ABA-specific suppressor T cells adoptively transfer ABA-specific suppression of D T H to syngenic recipients. T h e development of suppressor T cells in this system ~-~ and in the 4-hydroxy-3-nitrophenyl acetyl (NP) system, studied also in our laboratory with M a r t i n DorP, involves complex interactions of three sets of T cells in a regulatory circuit under the control of both IgH and H-2 genes. The first set of suppressor T cells, which we have termed Ts~, is induced by the intravenous administration of ABA-