Proceedings of the National Academy of SciencesVol. 66, No. 4, pp. 1127-1135, August 1970

Cells Involved in Cell-Mediated and TransplantationImmunity, II. A Consideration of the Functional

Identity of the Cells Involved in Both Humoral and Cell-Mediated Immunity: A Phylogenetic Approach

Maxwell Richter*DIVISION OF IMMUNOCHEMISTRY AND ALLERGY, MCGILL UNIVERSITY CLINIC, ROYAL VICTORIA

HOSPITAL, MONTREAL, QUEBEC

Communicated by Wilder Penfield, May 8, 1970

Abstract. The literature concerned with the types of cells that participate inthe humoral and cell-mediated immune response has been reviewed. It is postu-lated that the initial cells that are involved in mediating both types of immunityare functionally identical in that both are antigen-reactive cells. In the caseof the humoral immune response, the interaction of the antigen-reactive cellswith the antigen leads to the release or transfer of "information" to the antibody-forming cell, resulting in the synthesis and secretion of antibody molecules. Inthe case of cell-mediated immunity, it is considered that the primitive antigen-reactive cell itself transforms into the sensitized cell which infiltrates the site ofantigen administration.

A previous communication dealt with the relationship between the cells me-diating the humoral immune response and those cells whose immunologic functionis specifically neutralized in the induction of the state of immunologic tolerance.'An attempt was made to unify these apparently diametrically opposed immuno-logical states at the cellular level. Recent findings demonstrating the involve-ment of multiple cell types in the induction of the primary immune responsein the mouse2-5 and the rabbit6 support the concept of multicellular pathwaysleading to the humoral immune response.7 These pathways may consist of onecell only-antibody-forming; two cells-antigen-reactive and antibody-forming;and three cells-processing (macrophage?), antigen-reactive, and antibody-form-ing.7 The nature of the antigen constitutes the determining factor as to thecell pathway it will activate. The antigen-reactive cell is morphologically identicalto the antibody-forming cell,8 the lymphocyte nature of which has been welldocumented.9-11 However, these two cells have unique immunologic functions-the antigen-reactive cell possessing the capacity to recognize or cognize thenative or processed antigen and releasing "information" which stimulates theantibody-forming cell to synthesize and secrete antibody. Immunologic toler-ance has been shown to involve the inactivation or destruction of the specificallydirected antigen-reactive cells with the result that no "information" is passedon to the antibody-forming cell.7' 12The aim of this report is to unify the fields of humoral and cell-mediated im-

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munity insofar as the cell-types and intercellular reactions are concerned. Noattempt will be made to delve into the actual intra-cellular events which governthese two types of immune states. A number of excellent monographs'3" 4 andreview articles"-'7 and a speculative but profound and provocative article byHumphrey'8 have served to provide the author with the stimulus to present thisconcept.

In terms of the phylogeny of the immune response, the cell-mediated immuneresponse would appear to be the more primitive as there are indications of aninflammatory-type resistance having evolved in the lower animal species, suchas the invertebrates, in the absence of circulating antibodies which generallycharacterize immunity in the higher vertebrates.'9-2' Cell-mediated immunityappears to be the immunity of choice with respect to the generally noninvasiveorganisms-those which tend to localize within a particular organ. A classifi-cation of such microorganisms would include the fungi, rickettsia, viruses, proto-zoa, helminths, and some bacteria. Under these circumstances, it would beeconomical for the host organism to create cells which would be specifically at-tracted to the focus of infection, to either liberate an agent specifically toxictoward the invading organism or physically interact with the latter and even-tually wall off the infected area. It would be very extravagant on the part ofthe body to provide cells in a distant organ which would synthesize vast numbersof antibody molecules to combat a localized invader. In a review dealing withthe immune mechanisms in helminth infections, Soulsby22 states that there islittle evidence in nematode and trematode infections to show that circulatingantibody is concerned in protective immunity. Furthermore, although littleinformation exists with respect to the importance of white cells in the immuneresponse, the fact that they occur in large numbers at the site of an immunologicreaction between the host and the parasite is probably not a fortuitous finding.22On the other hand, a very large number of specifically sensitized cells would berequired to combat a disseminated or generalized infection, especially when it isalso accompanied by the secretion of exotoxins. To combat this type of infec-tion, the host has evolved a specific defense mechanism based on the secretion ofantibody molecules which circulate and meet the organism or toxin anywherein the body and there neutralize it. This type of immune mechanism permitsa conservation of the cell population with a concommitant lower expenditure ofenergy by the host since the energy expended to synthesize a large number ofantibody molecules is of several orders of magnitude less than is necessary forthe proliferation of a vast army of specifically sensitized cells. However, sinceimmunity mediated by humoral antibody is dependent upon complement inorder to successfully induce the lysis and death of the invading microorganism, ithad to await the evolution of the complement system before it could becomeeffective and displace cell-mediated immunity. It has been suggested thatcomplement evolved among the lower vertebrates.23 It is therefore of more thanacademic interest to note that antibody synthesis appears to have evolved amongthe lower invertebrates. However, humoral immunity in the invertebratesand lower vertebrates is independent of the complement system and constitutesa modified or primitive cytotoxic system.'1920'23

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It has been the experience of a large number of investigators that the inhibitionor delay of onset of the humoral immune response results in the unmasking andfacilitation of the cell-mediated response. Thus, cell-mediated immunity ratherthan humoral immunity will result by varying the route of antigen administra-tion,24 by subjecting the animal to a dose of total body irradiation capable ofinhibiting antibody formation,25-29 or by administering a small amount of theantigen in the form of an antigen-antibody complex.30-32 In each of these cases,the humoral immune response is very much delayed in onset and is characterizedby a low concentration of circulating antibodies. On the other hand, the induc-tion of a state of cell-mediated immunity can be suppressed if the antigen is firstadministered in such a way as to evoke a humoral response.33-36 In fact, Crowleand Hu37 demonstrated that they could inhibit the occurrence of cellular im-munity (delayed skin reaction) if they passively immunized the animal before-hand with homologous antiserum.

In retrospect, it might have been anticipated that the presence of circulatingantibodies would normally prevent the manifestation of cell-mediated immunitydirected toward the same antigen from being evident, probably as a result ofneutralization of the antigen by circulating antibody before it can interact withthe cell that mediates cellular immunity or the delayed hypersensitivity reaction.However, it could be postulated that these two types of immune mechanismscan only exist in series, and not in parallel, and that the cell(s) which wouldnormally be stimulated to participate in the cell-mediated response could be di-verted toward the synthesis of humoral antibody. That this is not the case wasdemonstrated by Crowle and Crowle,38 who observed that the lymphoid cellsand the serum of a guinea pig immunized with ovalbumin could simultaneouslytransfer cell-mediated immunity (delayed hypersensitivity) and Arthus reactiv-ity (humoral immunity), respectively, to normal recipients. More recently,Brostoff and Roitt39 demonstrated that humoral and cell-mediated immunitycan coexist in the untreated grass-sensitive individual since the latter couldgive both a wheal and flare (immediate) skin reaction (humoral immunity) aswell as a delayed skin reaction (cell-mediated immunity) if the former were in-hibited by the administration of antihistaminics. Thus, it would appear thathumoral and cell-mediated immunity are not mutually exclusive states inducedby antigen stimulation.In order to bridge the void that exists with respect to the cell types involved

in manifesting humoral and cell-mediated immunity, it is suggested that theantigen-reactive cell constitutes the basic cell for both types of immune responses.This cell concerned with evoking humoral immunity is considered to be a morehighly evolved cell of the short-lived variety of lymphocyte, and to inhabit aparticular organ, such as the bone marrows058 or the thymus,2-5 rather than bein the circulation. The antigen-reactive cell concerned with evoking cell-me-diated immunity may be more primitive with respect to antigen-reactive cellfunction, and it may be of the long-lived variety of lymphocyte. It is alsopresent in the circulation of the normal animal since peripheral leucocytes caninitiate a "graft-versus-host reaction" in the mixed leucocyte culture reaction.This consideration would permit an understanding of the radio-sensitive nature

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of the humoral,740,4' but not of the cell-mediated,24-26 immune response, since ashort-lived cell, because of its higher rate of metabolism and protein turnover,would be expected to be more susceptible to the deleterious effects of irradiationthan a long-lived cell.Assuming that the initial event in the induction of both types of immunity is

antigen recognition, is the mechanism of recognition the same and what coit-stitutes a recognition site on the antigen-reactive cell? Since the compositionand nature of the recognition site is not known with respect to either of the twotypes of immunity, it might be expedient to consider that the recognition sitesare essentially identical. This, in fact, has been suggested by Humphrey.'8In the case of humoral immunity, it is assumed that the recognition site on thevirgin antigen-reactive cell consists of an antibody molecule or at least the anti-gen-combining fragment that is configurationally complementary to that ofthe antigen. Interaction of this site with the specific antigen stimulates thecell to undergo blastogenesis and mitosis,42,43 with accompanying synthesis ofan excess of these "recognition sites" with their subsequent release from thecell, either free or combined with antigen (native or degraded) (Fig. 1). It isinteresting that Paul Ehrlich44 postulated the release of similar antigen-reactivemoieties from antibody-forming cells 70 years ago. This complex of recognition-

HUMORAL IMMUNITY

EVOLVED ARC

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RAPID ARC PROLUFERATION ANIRECOGNITION SITE PROUFERAT

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RELEASE OF RECOGNITION SITEAND DEATH OF ARC

AT~~~AAG-RECDO SITE A<CCOMPLEXaSUPER AG AFC2

ANTIBODY

CELL-MEDIATED IMMUNITY

PRIMIVE ORPRIMORDIAL ARC

long lived ARC + 0)AGlymphocyte

ION

AR

4 SLOW PROLIFERATION(2-3 wooes)

i '- RECOG SITE

S ILITTLE OR NO RELEASE OFRECOGNITION SITES

+ RECOGSITES

/ACTIVELYSENSITIZED

CELLIMMUNOLOGICALLYUNCOMMITTED

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MIGRATIONINHI4TORY FACTOR

INIITION OF JPROMOTES IFILTRATION OFCELL rATrIONINAR CELLS IN VIVO

FIG. 1.-The relationship between humoral and cell mediated immunity.

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site antigen may constitute the superantigen or immuno-carrier that has beendetected in the circulation of the immunized animal.45'46 This complex wouldpossess a high affinity for the antibody-forming cell with which it would interactand trigger off the proliferative and transformational events culminating inhumoral antibody formation. On the other hand, it is postulated that the moreprimitive cell-mediated immunity has not evolved as far as the antibody-formingcell. Here, the cell that participates in the infiltrative reaction of cellular im-munity is, in reality, the antigen-reactive cell which does not liberate its recogni-tion sites to an appreciable degree after the interaction with the antigen. Ra-ther, this cell transforms into the sensitized cell. However, the "recognitionsites" that were liberated as a result of cell death or other cause are capable ofpassively sensitizing immunologically uncommitted lymphoid cells (Fig. 1).The findings of Freedman et al.47 and Perey et al.48 support this interpretation.Freedman et al. observed that cell-free extracts of peripheral leucocytes obtainedfrom PPD-negative and positive individuals could agglutinate red cells sensitizedwith PPD, although the titers of extracts of cells of PPD-negative individualswere uniformly lower than those of cells from PPD-positive individuals. How-ever, since the sera of these individuals also possessed antibodies in high titer toPPD, it may be that Freedman et al. detected cytophilic antibody. Furthermore,the fact that tuberculin-negative individuals possessed antibodies to PPD isgenerally considered to represent the consequence of subclinical immunizationwith tuberculin. Perey et al.,48 in a recent communication, reported that theycould passively transfer skin homograft immunity in chickens with plasma ob-tained from sensitized x-irradiated bursectomized (agammaglobulinemic) donors.They suggest that circulating antibodies do not appear to play a role in thetransfer of cell-mediated immunity and that the irradiated sensitized cells in theirradiated donor probably released a substance(s) into the circulation thatcould confer homograft immunity onto normal cells in a recipient animal. Theyconsider that this substance (recognition sites?) is quickly removed by receptorsites on other lymphoid cells but they did not investigate how long this substancecould be detected in the circulation following x-irradiation.Although Nelson and Boyden49 claim that cytophilic antibody is not involved

in the mediation of the delayed hypersensitivity reaction, Amos et al.50 havedemonstrated that guinea pig gamma 2 cytophilic antibodies can effect inhibitionof macrophages in the presence of the specific antigen. It is generally agreed",that the two biologically active agents concerned transfer factor and migrationinhibitory factor-are not related substances and that the migration inhibitoryfactor is released as a result of the interaction between the sensitized cell (transferfactor?) and the antigen. The migration inhibitory factor then acts on normalmacrophages to immobilize them. Whether this factor acts in an immunolog-ically specific or nonspecific fashion cannot be ascertained at the present time,although Amos and Lachmann5l have recently demonstrated that antigen isrequired for the inhibition of migration of normal macrophages by cell-freesupernatants (migration inhibitory factor?) obtained from cultures of sensitizedguinea pig lymph node cells and antigen.

Evidence in favor of the functional and biological, if not chemical, identity

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of the recognition sites on the antigen-reactive cell which mediates humoralimmunity and the sensitized cell which mediates cellular immunity emanatesfrom recent observations on the migration capacities of lymphoid cells in vitroin the presence of antigen. A large number of investigators have demonstratedthat interaction of peritoneal exudate cells of sensitized (i.e., old tuberculin)animals with the antigen in vitro results in inhibition of migration of thesecells. 15,52-54 Falk and Falk55 have observed that the migration of normal ratthymus cells in vitro can be inhibited by a number of antigens of divergent com-position, although the cells of the other lymphoid organs were not so affected.Preliminary observations with the rabbit in this laboratory suggest that thein vitro migration of normal rabbit bone marrow cells can also be inhibited byantigens.56 It is interesting to note that the prime organ sources of the antigen-reactive cell appear to be the thymus in the mouse2-5 and the bone marrow inthe rabbit.'4042,43,57,58 These findings strongly suggest that the antigen-reactivecell that mediates the humoral immune response can interact with the antigenin vitro as a result of which their migration, and that of the other bystander cells,is impeded or inhibited. Falk59 has also observed that the in vitro migration ofnormal human thymus cells obtained from a tuberculin-negative individual canbe inhibited by incubation with PPD, although thymus cells obtained from atuberculin-positive individual could not be so affected by PPD in vitro, which sug-gests that the thymus may indeed be the source of virgin antigen-reactive cell inman. This finding suggests that the human thymic antigen-reactive cell vacatesthe thymus, just as that cell in the rabbit vacates the bone marrow after antigenicstimulation.7'40 It would therefore appear that the recognition sites on thesurface of the virgin precommitted antigen-reactive cell mediating the humoralimmune response impart to the cells the property which permits their reactionwith the antigen to manifest itself in a manner indistinguishable from that ofthe interaction of the antigen with the "sensitized cell" participating in cell-mediated immunity, that is, inhibition of cell migration in vitro.

It is interesting to note that only 1-4% of the cells infiltrating a site of a de-layed hypersensitivity reaction have been shown to be sensitized cells.60-62 Sincemost of the infiltrating cells were not originally sensitized to react with the anti-gen, they therefore must have been passively sensitized as a result of interactionwith a factor released by the sensitized cell (migration inhibitory factor?) whichwould render them capable of interacting with the antigen and of being im-mobilized at the site of injection of the antigen (Fig. 1). Falk et al.63 arrivedat a similar conclusion on the basis of results obtained with normal and sensitizedrat spleen cells in vitro. Only supernatants of cultures of sensitized cells with theantigen (sheep red cells or allogeneic spleen cells) could inhibit the migration ofsyngeneic cells in vitro. Since the inhibition of migration affects the whole cellpopulation, they concluded that an active substance is released from sensitizedlymphocytes incubated with the antigen which can then react with "innocentbystander cells" in such a way as to prevent their migration.f3 Such a mech-anism would provide an explanation for an apparently insoluble dilemma-howto account for the large percentage of cells capable of participating in the cell-mediated reaction. Although the clonal selection theory would not permitmore than 1/104-10 antigen-reactive cells mediating the humoral immune

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response to be specifically precommitted with respect to any one antigen,'2'64-66it has nevertheless been observed that as many as 1-2%o of virgin cells are capableof mediating cellular immunity.67'6i8

Additional evidence suggesting the functional identity of the cells mediatinghumoral and cellular immunity derives from studies on the blastogenic capacitiesof lymphoid cells. It is generally agreed that a state of delayed hypersensitivitymust exist in order for sensitized or immune cells to undergo blastogenesis andmitosis in the presence of the antigen.39",9-7' Furthermore, normal rabbit bonemarrow lymphocytes42'43 and normal mouse thymic cells7" are also capable ofundergoing blastogenesis upon stimulation with antigens. Since the normalcells exhibiting this activity are considered to be virgin, precommitted antigen-reactive cells, it would appear that the normal antigen-reactive cells mediatinghumoral immunity cannot be distinguished from the sensitized cell mediatingcellular immunity on the basis of the blastogenic response to antigen.One may indeed speculate as to whether the "potentiating factor" released

from cultures of normal cells, recently described by Janis and Bach,73 might notin fact be "recognition sites" capable of passively sensitizing other uncommittedlymphoid cells. This substance, released by peripheral blood lymphocytes inculture, is capable of potentiating the blastogenic effect of antigens (i.e., PPD)in vitro.Although it has been demonstrated that the antigen-recognition site on an

immune cell is antigenically an immunoglobulin molecule or fragment,74 noevidence has as yet been presented to suggest that the recognition site on thevirgin immunocompetent cells is protein in nature. Lawrence has presentedevidence" that "transfer factor" mediating cellular immunity is probably apolynucleotide. If "transfer factor" is not any antibody molecule but rather a"recognition site" released from the virgin antigen-reactive cells mediatingcellular immunity (Fig. 1), then might not the recognition site on the surface ofthese cells mediating humoral immunity possess the same composition? Thepolynucleotides may, in fact, represent a specifically coded sequence of nucleo-tides, capable of reacting with antigen. The antigen-reactive cell would thenrelease the complex composed of recognition site and antigen which would beaccessible to the antibody-forming cell and would transfer specific informationto the antibody-synthesizing apparatus of the antibody-forming cell. This in-formation would be translated by the latter cells into the amino acid sequenceof the antibody-reactive site on the antibody molecule which would be configura-tionally complimentary to the antigenic site on the antigen molecule. Thisinformation, in the form of specific polynucleotides, would cause an alterationin the basic ribosomal RNA template followed by a corresponding alterationin the synthesis of antibody immunoglobulins. Such a mechanism would pro-vide for the recruitment of uncommitted antibody-forming cell when the situationwould require it. The chromosomal DNA would not be affected at all andtherefore it would not be necessary to postulate the transmission of immunologicinformation to progeny cells. Thus, this concept would conform with the tem-plate theory of antibody formation postulated by Breinl and Haurowitz 40 yearsago7' and subsequently modified by Haurowitz.76The objective of this communication was to unify the fields of humoral and

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cell-mediated immunity. Evidence has been presented to support the postu-lated scheme. As the cells and mechanisms presented above are amenable tolaboratory investigation and verification, it should be possible to determine thevalidity of the proposed mechanisms within a relatively short period of time.In any case, this presentation should provide a stimulus for a more penetratingand analytical approach toward the elucidation of the cells and cell-interactionsconcerned with the humoral and cell-mediated immune responses.

Abbreviation: PPD, purified protein derivative from Mycobacterium tuberculosis.* Medical Research Associate, Medical Research Council, Canada.1 Richter, M., Proc. Nat. Acad. Sci. USA, 64, 75 (1969).2 Claman, H. N., and E. A. Chaperon, Transplant Rev., 1, 92 (1969).3 Davies, A. J. S., Transplant Rev., 1, 43 (1969).4Taylor, R. B., Transplant Rev., 1, 114 (1969).5 Miller, J. F. A. P., and G. F. Mitchell, Transplant Rev., 1, 3 (1969).6 Richter, M., and N. I. Abdou, J. Exp. Med., 129, 1261 (1969).7Abdou, N. I., and M. Richter, Advan. Immunol., in press.8 Abdou, N. I., and M. Richter, J. Exp. Med., 130, 141 (1969).9 Gowans, J. L., and D. D. McGregor, Progr. Allergy, 9, 1 (1965).

10 Wilson, D. B., and R. E. Billingham, Advan. Immunol., 7, 189 (1967).1 Dutton, R. W., Advan. Immunol., 6, 254 (1967).12 Abdou, N. I., and M. Richter, J. Exp. Med., 130, 165 (1969).13 Turk, J. L., ed., "Delayed Hypersensitivity: Specific Cell-Mediated Immunity," Brit.

Med. Bull., 23 (1) (1967).14Turk, J. L., Delayed Hypersensitivity (Amsterdam: North Holland Publishing Co., 1967).15 Lawrence, H. S., Advan. Immunol., 11, 196 (1969).1 Mackaness, G. B., and R. V. Blanden, Progr. Allergy, 11, 89 (1967).17 Bloom, B. R., and M. W. Chase, Progr. Allergy, 10, 151 (1967).18 Humphrey, J. H., Brit. Med. Bull., 23, 93 (1967).19 Good, R. A., and B. W. Papermaster, Advan. Immunol., 4, 1 (1964).2' Gray, H. M., Advan. Immunol., 10, 51 (1969).21 Smith, R. T., P. A. Miescher, and R. A. Good, ed., Phylogeny of Immunity (Gainesville:

University of Florida Press, 1966).22 Soulsby, E. J. L.. Advan. Immunol., 2, 265 (1962).23 Gewurz, H., J. Finstad, L. H. Muschel, and R. A. Good, in Phylogeny of Immunity, ed.

Smith, R. T., P. A. Miescher, and R. A. Good (Gainesville: University of Florida Press, 1966),p. 105.

24 Szenberg, A., and N. L. Warner, Brit. Med. Bull., 23, 31 (1967).25 Uhr, J. W., and M. Scharff, J. Exp. Med., 112, 65 (1960).26 Salvin, S. B., and R. F. Smith, J. Exp. Med., 109, 325 (1959).27 Uhr, J. W., and M. Scharff, J. Clin. Invest., 38, 1049 (1959).28 Salvin, S. B., and R. F. Smith, J. Exp. Med., 111, 465 (1960).2" Pappenheimer, A. M., Jr., M. Scharff, and J. W. Uhr, in Mechanisms of Hypersensitivity,

ed. Shaffer, J. H., G. A. Legrippo, and M. W. Chase (Boston: Little, Brown & Co., 1959).3 Uhr, J. W., S. B. Salvin, and A. M. Pappenheimer, Jr., J. Exp. Med., 105, 11 (1957).31 Benacerraf, B., and P. G. H. Gell, Immunology, 2, 53 (1959).32 Salvin, S. B., J. Exp. Med., 107, 109 (1958).33 Boyden, S. V., Int. Arch. Allergy Appl. Immunol., 10, 65 (1957).84 Asherson, G. H., and S. H. Stone, Immunology, 9, 205 (1965).36 Loewi, G., E. J. Holborow, and A. Temple, Immunology, 10, 339 (1966).3' Boyden, S. V., Brit. J. Exp. Pathol., 38, 611 (1957).37 Crowle, A. J., and C. C. Hu, J. Immunol., 94, 555 (1965).38 Crowle, A. J., and C. M. Crowle, J. Allergy, 32, 302 (1961).39 Brostoff, J., and I. M. Roitt, Lancet, JI, 1269 (1969).40 Abdou, N. I., and M. Richter, J. Exp. Med., 129, 757 (1969).41 Taliaferro, W. H., L. G. Taliaferro, and B. M. Jaroslow, in Radiation and Immune Mecha-

nisms (New York: Academic Press, 1964).42 Singhal, S. K., and M. Richter, J. Exp. Med., 128, 1099 (1968).

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43Singhal, S. K., and H. Wigzel, J. Exp. Med., 131, 149 (1970).44 Marquardt, M., in Paul Ehrlich (London: William Heinemann, 1949), p. 68.45 Michelazzi, L., I. Baldini, A. Novelli, and G. Nanni, Nature, 205, 194 (1965).46 Michelazzi, L., G. Nanni, I. Baldini, and A. Novelli, Experientia, 20, 447 (1964).4 Freedman, S. O., R. Turcotte, A. J. Fish, and A. H. Sehon, J. Immunol., 90, 52 (1963).48 Perey, D. Y. E., J. M. Dupuy, and R. A. Good, Transplantation, 9, 8 (1970).49 Nelson, D. S., and S. V. Boyden, Brit. Med. Bull., 23, 15 (1962).50 Amos, H. E., B. W. Gurner, R. T. Olds, and R. R. A. Coombs, Int. Arch. Allergy, 32, 496

(1967).51 Amos, H. E., and P. J. Lachmann, Immunology, 18, 269 (1970).52 George, M., and J. H. Vaughan, Proc. Soc. Exp. Biol., 3, 314 (1962).5'3 David, J. R., S. Al-Askari, and H. S. Lawrence, J. Immunol., 93, 264 (1964).54"Bloom, B. R., and B. Bennett, Science, 153, 80 (1966).55 Falk, J. A., and R. E. Falk, Ann. Roy. Coll. Phys. Surg. Canadla, 3, 29 (1970).5 Likhite, V., and M. Richter, unpublished results.57 Abdou, N. I., B. Rose, and M. Richter, J. Exp. Med., 130, 867 (1969).5 Richter, M., B. Rose, and N. I. Abdou, Int. Arch. Allergy, 38, 269 (1970).59 Falk, R. E., personal communication.60 Feldman, J. D., and J. S. Najarian, J. Immunol., 91, 306 (1963).61 Turk, J. L., and J. Oort, Immunology, 6, 148 (1963).62 McCluskey, R. T., B. Bfnacerraf, and J. W. McCluskey, J. Immunol., 90, 466 (1963).63 Falk, R. E., L. Collste, and G. Moller, Surgery, 66, 51 (1969).64 Sulitzeanu, D., and D. Naor, Int. Arch. Allergy, 35, 564 (1969).65 Ada, G. L., and P. Byrt, Nature, 222, 1291 (1969).6 Byrt, P., and G. L. Ada, Immunology, 17, 503 (1969).67 Nisbet, N. W., M. Simorqsen, and M. Zaleski, J. Exp. Med., 129, 459 (1969).68 Wilson, D. B., J. L. Blyth, and P. C. Nowell, J. Exp. Med., 128, 1157 (1968).69 Naspitz, C. K., and M. Richter, Progr. Allergy, 12, 1 (1968).70 Mills, J. A., J. Immunol., 97, 239 (1966).7' Zweiman, B., Immunology, 13, 315 (1967).7 Gershon, R. K., V. Wallis, A. J. S. Davies, and E. Leuchars, Nature, 218, 380 (1968).7 Janis, M., and F. Bach, Nature, 225, 238 (1970).74 D1aguillard, F., and M. Richter, J. Exp. Med., 131, 119 (1970).75 Breinl, F., and F. Haurpwitz, Z. Physiol. Chem., 192, 45 (1930).76 Haurowitz, F., Biol. Rev., 27,-247 (1952).

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