Showing papers in "Immunological Reviews in 1978"

The Immune Response Genes of the Major Histocompatibility Complex

Abstract: dinitrophenyl poly-L-lysine complete Freund's adjuvant delayed-type hypersensitivity immune response immune suppression bovine serum albumin ovalbumin poly (L-glu^-L-lys\"\") poly (L-glu'^-L-ala*\") poly (L-gluTM-L-tyr5») guinea pig albumin major histocompatibility complex guinea pig major histocompatibility complex major histocompatibility complex-linked poly (I^glu^-L-ala^o-L-tyr'o) methylated bovine serum albumin thymus-derived (T) lymphocytes B lymphocytes plaque-forming cells peritoneal exudate T enriched lymphocytes trinitrophenyl cytolytic T lymphocjfte(s) poly (L-glu5«-L-lys^-L-phe') poly (L-glu«-L-lys\"-L-alai») T-lymphocyte derived suppressor factor C57BL/6 C57BL/10 poly (I^tyr, L-glu)-poly-DI^ala-poly-L-lys poly (L-tyr, L-glu)-poly-L-pro-poIy-I^lys poly (L-phe, L-glu)-poly-DL-ala-poly-L-lys poly (L-his, I^glu)-poly-DL-ala-poly-L-lys

Determinant selection and macrophage function in genetic control of the immune response

Abstract: The immune response to insulin, in both mouse and guinea pig, is under control of H-linked immune response genes. When immunized with either pork or beef insulin in CFA, both strain 2 and 13 guinea pigs respond by antigen-specific lymphocyte proliferation and synthesis of specific antibody. The specificities of the elicited antibodies and indistinguishable between these inbred strains. By constrast, strain 2 T cells recognized a distinct region of the A chain alpha loop consisting of amino acid residues 8, 9 and 10, while strain 13 T cells see an as yet undefined region of the B chain. H2b (A chain alpha loop responder) and H2d (B chain responder) mice similarly discriminate which areas of the molecule are recognized by their T lymphocytes. The function of the Ir gene in both the guinea pig and mouse appears to be an intramolecular selection of discrete regions within the antigen for recognition by the T cell. The data presented suggest that this function operates at the level of the macrophage.

The Regulation of Lymphocyte Functions by the Macrophage

Abstract: Macrophages may exert a regulatory influence at various stages in the life of the lymphocyte - they may influence the non-antigen-driven differentiation of lymphocytes - as exemplified by the effects on thymic differentiation; they may establish the mode and form of antigen to be presented or recognized by the lymphocyte; may regulate the lymphocyte's antigen-driven functions. Each of these critical regulatory steps needs explaining in molecular terms and integrated and placed in the context of the other regulatory functions of lymphocytes. The control of secretion of MP is an eloquent example of the molecular complexities and the intricate congrol mechanisms - internal and external - operating at each step of each regulatory process. A final comment concern the question of macrophage heterogeneity. Is the same cell performing all the functions of degradation, presentation, and secretion - or cytotoxicity? Or do we have subpopulation, each with a different role? This issue is not settled. The unitarians argue that the phagocytes pass through different stages of differentiation and that each function may become more or less prominent at each stage. Certainly, the manner in which each macrophage function is assayed can condition the outcome: for antigen presentation, one adds 1 % of macrophages to cultures of spleen cells; for cytotoxic assays, the figure is 50 to 100 macrophages per tumor cell! It is our feeling that until such time as membrane molecules are identified and used as probes for differentiation or for identification of subsets we will not resolve this issue. Along these lines, macrophages have been found to have Ia antigens (Hammerling et al. 1975, Schwartz et al. 1976) and can be divided into two sets on the basis of the presence or absence of Ia. Dorf and I have found - by cytotoxicity - that only about 35 to 50% of peritoneal macrophages bear Ia molecules (Dorf & Uanue 1977). Exceptionally, some exudates will bear up to 75% positive cells. Neither Ia-positive nor Ia-negative macrophages change significantly after prolonged periods of culture. Whether these results indicate two defined subsets of macrophages is now being investigated.

The Influence of Thymus H-2 Antigens on the Specificity of Maturing Killer and Helper Cells

Abstract: The subject matter of this review is highly restricted. It covers only those T cells which exhibit a dual specificity, i. e. antigen specific T cells which are also specific for a particular self major histocompatibility complex (MHC) structure. In the mouse, where the MHC is called the H-2 complex, such T cells are referred to as H-2 restricted cells. In a functional way, H-2 restriction means that T cells from an U-2^ animal immunized against a foreign antigen (call it X) can perform when they are presented with X on H-2t' cells, but are apparantly \"blind\" to the correct antigen, X, on H-2'' or H-2'' cells. Killer and helper T cell functions are H-2 restricted! Obviously a killer cell has to focus its attention on cell membrane antigens to perform its effector function—killing abnormal cells. The signal from a helper T cell to a B cell also needs to be delivered at the B cell surface. The advantage of the dual specificity of these classes of T cells may be just this—to ensure that they do focus their attention on cell-membrane-bound antigen and avoid having their effector functions dissolved out by fruitless interactions with soluble antigens.

Mechanisms by which activated macrophages inhibit lymphocyte responses.

Abstract: During the past decade it has become apparent that macrophages are not just passive carriers of antigen to lymphocytes. Macrophages and macrophage products stimulate responses of Tand B-lymphocytes in vitro (van Furth 1975, Rosenthal 1975, Nelson 1976). However, when macrophages are present in supraoptimal numbers they can inhibit immune responses. This has been shown for primary antibody production ia culture (Perkins & Makinodan 1965, Parkhouse & Dutton 1966, Diener et al. 1970); mitogen induced polyclonal Bor T-lymphocyte responses (Folch & Waksman 1973, Waldman & Gottlieb 1973, Bakd & Kaplan 1977); mixed lymphocyte reactions (Fembach et al. 1976, Oehler et al. 1977); and the generation of cells cytotoxic for tumour cells and allogeneic lymphocytes (Kxmg et al. 1977, Weiss & Fitch 1977). These inhibitory effects of macrophages are non-specific in the sense that they are exerted against a variety of Tand B-ljnmphocyte responses to antigens and mitogens. However, the functional state of macrophages affects both their ability to increase and to suppress immune responses. As pointed out previously (Allison & Davies 1975), macrophages can be activated in several ways to produce a variety of responses, defined in biochemical or functional terms. These are not always equivalent, so that is necessary in each case to define the activating agent used and the responses measured. Macrophage-activating agents include various organisms producing infectious diseases, some of which act as polyclonal mitogens and some as immunosuppressive agents. Many adjuvants exert their primary effects on macrophages. Often the immunopotentiating and immunosuppres-

Role of H‐2 Gene Products in the Function of T Helper Cells from Normal and Chimeric Mice in Vivo1

Abstract: The decisive role played by the major histocompatibility complex (MHC) in T cell recognition is now well established. MHC determinants affect a spectrum of T cell functions, including cell-mediated lympholysis (CML) against virus-infected or hapten-modified target cells (Shearer et al. 1975, Zinkernagel & Doherty 1975), collaborative interactions with specific B lymphocytes (Kindred & Shreffler, 1972, Katz et al. 1973), proliferative responses to antigen-pulsed macrophages in vitro (Rosenthal & Shevach 1973) and the expression of delayed-type hypersensitivity (DTH) (Miller et al. 1976). By these parameters, most workers have concluded that T cells fail to recognize antigen presented in association with foreign MHC determinants. This has led to the notion that the T cell repertoire is restricted to recognition of antigen complexed to "self" MHC determinants.

Different functional specificity repertoires for suppressor and helper T cells.

Abstract: BIO = C57BL'1O strain mice BlOA = C57BiyiO.A strain mice CB-2 = second cyanogen-bromide fragment from GZ, amino acid residues 3-92 CFA = complete Freund's adjuvant FL = fiuorescein GZ = j8-galactosidase HBL = chicken egg-white lysozyme (other abbreviations of lysozymes ending in -EL appear in Table VIII) Ir genes = immune response genes PETLES = Peritoneal-exudate T-Iymphocyte enriched cells PFC = Plaque forming cell RCM-HEL = reduced, carboxymethylated chicken lysozyme RCM-Lji = reduced, carboxymethylated cyanogen-bromide fragment a.a. residues 13-105 from chicken lysozyme SD = suppressor determinant Th = helper T-cell subpopulation T» = suppressor T-cell subpcpulation

Structure-function relationships in human immunoglobulin E.

Abstract: The current interest in IgE has evolved from the discovery that antibodies of this minor class of immunoglobulin carry the biological, immunochemical and physical characteristics of reaginic antibodies. The important property of IgB antibodies which allows them to mediate Type I immediate hypersensitivity is their ability to bind reversibly with high affinity to specific membrane receptors on basophils and mast cells. Combination of specific cell-bound antibody with antigen triggers a series of events which ultimately leads to the release of vasoactive amines and other pharmacologically active substances responsible for the clinical manifestations of hypersensitivity. The nature of these intracellular events is poorly understood. Indeed a substantial number of people may ask why these events need exist at all, particiilarly when they are suffering through the ragweed or other airborne-antigen season! In other words the physiological importance of IgE is not known, although it has been implicated in resistance to parasitic infestation.

Mechanisms of Reaginic Hypersensitivity and IgE Antibody Response

Abstract: Immunoglobulin E was found when we were studying reaginic antibody in the serum of hay fever patients and was identified as a carrier of reaginic antibody activity (Ishizaka et al. 1966a, b, Ishizaka & Ishizaka 1967). An injection of purified IgE preparation from ragweed sensitive individuals into normal skin resulted in the sensitization of the skin site for the PrausnitzKiistner (P-K) reaction, and the removal of IgE antibody in the serum of atopic patients by anti-IgE was accompanied by loss of sensitizing activity. Subsequent studies have shown that association of reaginic activity with IgE was found not only in the ragweed system but also in the other allergenreagin systems. Antigenic analysis of the immunoglobulin (Ishizaka et al. 1967d) and identification of a imique myeloma protein ND as an E myeloma protein (Johansson & Bennich 1967, Bennich et al. 1968) established that IgE represents a unique immunoglobulin class. Since then, effort in our laboratory has been focused to study immtinological mechanisms of reaginic hypersensitivity reactions. Identification of reaginic antibody as IgE provided immunochemical approaches to solve the problems. In the past several years, we have also studied cellular events in the IgE antibody response. Although the two subjects are unrelated, we shall summarize our findings on the immunological mechanisms of IgB-mediated reactions first, followed by mechanisms of IgE antibody response.

T lymphocyte numbers and function in human IgE-mediated allergy.

Abstract: The discovery that reaginic antibody activity is associated with a unique immunoglobulin class, IgE, in humans (Ishizaka et al. 1966, Johansson & Bennich 1967) was soon followed by demonstrations of IgE also in various animals. This opened the field of studying regulatory mechanisms in reagin synthesis. It was found that the production of IgE antibody is dependent on genetic factors (Levine & Vaz 1970), adjuvants (Revoltella & Ovary 1969, StrannegSrd & Chan 1969), route of antigen administration (Strannegkrd & Yurchision 1969a) and antibodies belonging to other immunoglobuUn classes (StrannegSrd & Belin 1970, 1971, Tada & Okumura 1971, Ishizaka & Okudaira 1972). Characteristic features of IgE production were also found as regards antigen dose dependency (Levine & Vaz 1970, StrannegSrd 1973). In several respects IgE synthesis was found to be markedly different from the production of IgG and IgM antibody (Tada 1975). The distinctive features of IgE synthesis have been summarized by Tada (1975) and Ishizaka (1976). It is evident that IgE synthesis is dependent on cooperation between T and B cells (Okumura & Tada 1971, Michael & Bernstein 1973). T helper cells as well as T suppressor cells appear to exert strong influences on the IgE response. The important role of antigen-specific regulatory T cells has been established in a series of experiments performed by Tada and his associates (Tada 1975). Several lines of evidence suggest that antigen non-specific T lymphocytes also regulate IgE antibody responses. In studies of rabbit reagin response StrannegSrd & Yurchision (1969b) found that treatment of rabbits with 6-mercaptopurin after injection of a hapten-protein conjugate markedly enhanced and prolonged the

The role of I region gene products in macrophage - T lymphocyte interaction.

Abstract: The macrophage first gained recognition in the early 192O's and 193O's as the cell responsible for clearing antigen and synthesizing antibody (Sabin 1923). Its importance to the immune response faded with the realization that lymphocytes and not macrophages were the origin of antibody molecules and it was not until the early 196O's that experiments suggested that antigen processing by the macrophage was required for stimulation of immunocompetent lymphocytes (Fishman & Adler 1963). This renewed interest, however, was short lived when it was demonstrated that antigens could be recognized by lymphocytes. Furthermore, although lymphocytes could interact with macrophage bound antigen it did not appear critical that this antigen be processed, or structurally altered, by the macrophage.

The Role of Adherent Cells in B and T Lymphocyte Activation

Abstract: Macrophages have been found to be of importance in several difierent immunological reactions. Thus, macrophages are required for induction of a primary immune response to heterologous red blood cells in vitro (Mosier & Coppleson 1968), and for a proliferative response induced in vitro to alloantigens (Alter & Bach 1970, Rode & Gordon 1970, Twormey et al. 1970), as well as for the developement of cytotoxic cells (Wagner et al. 1972, McDonald et al. 1973). Fxirthermore, macrophage and factors released by macrophages can induce proliferation in spleen cells and cause production of polyclonal immunoglobuiins (Lemke & Opitz 1976, Moller et al. 1976, Opitz et al. 1976). In all these systems, however, fetal calf serum together with 2-mercaptoethanol (2-ME) can substitute for macrophages, indicating a nonspecific function of adherent cells (Chen & Hirsh 1972, Bevan et al. 1974, Lemke & Opitz 1976). In this paper, we report on some effects of adherent cells on B and T cell activation induced by polyclonal cell activators, and we discuss the possible mechanisms behind the synergistic effect observed between B and T cell mitogens and adherent cells. In the experiments shown, Fi hybrids of the inbred mouse strains A/Sn and C57B1 or B10.5M were used, if not otherwise indicated. Cells were cultured senimfree in microcultures (usually triplicate cultures with 5 X 10* cells/0.2 ml of medium) and incorporation of ^H-thymidine was measured on day 2.

T Cells, T Cell Recognition Structures, and the Major Histocompatibility Complex

Abstract: la Ig KLH MHA MHC MLR PHA Abbreviations antilymphocyte serum bone marrow-derived lymphocjftes guinea pig counterpart of the murine H-2K and H-2D antigens bromodeoxyuridine cell mediated lysis concanavalin A radioactive chromium far right (distal to centromere) region of the H-2 complex dinitrofluorobenzene dinitrophenyl delayed type hypersensitivity Fc receptor fowl gamma globulin region of H-2 complex between S and D, defined by blood group locus H-2G graft-versus-host histocompatibility murine major H locus that defines the D region murine major H locus that defines the K region murine major H locus defined by specialities H-2.1 and H-2.28 and in or close to the D region; also called H-2D' region of H-2 complex between K and S, tentatively divided into subregions I-A, I-B, I-J, I-E. I-C a family of antigens produced by loci in the / region immunoglobulin keyhole limpet hemocyanin major histocompatibility antigen major histocompatibility complex mixed lymphocyte reaction phytohemagglutinin

Stimuli for the Production and Control of IgE in Rats

Abstract: In Hooded Lister rats IgE responses may be induced by administration of antigen together with one of a number of adjuvants. The primary IgE response may subsequently be enhanced either specifically by a further exposure to antigen (booster response) or non-specifically by infection with helminth parasites (potentiated response). In the latter case the enhanced response is associated with a great increase in total serum IgE. The primary response itself is not significantly influenced by variations in the general theme of conventional immunization, including dose or route of administration of antigen, or the nature of the adjuvant employed. The booster response however is inhibited, a) in rats primed with a 'large' (e.g. greater than 100 microgram EA) dose of antigen and B. pertussis, and b) rats primed with any dose of antigen given in Al(OH)3 or CFA, and c) following repeated booster doses of soluble (i.e. unadjuvanted antigen even at a dosage of a few picogrammes. It is thought that each of the stimuli generate antigen specific suppressor T cells. Live worm parasites selectively, but non-specifically, stimulate heterologous antigen primed IgE responses. The evidence suggests that it may be this non-specific IgE stimulating effect rather than the parasite specific IgE response per se which leads to the great elevation of total serum IgE. Other immunoglobulin classes are not elevated in the same way. The potentiated IgE response is not susceptible to the suppressive influence generated by previous administration of large or repeated doses of the heterologous antigen. On the other hand, a parasite specific regulatory mechanism acts to prevent repotentiation of the heterologous (but not the parasite specific or total IgE) responses following reinfection. These results are discussed in relation to the work of others in rats and other species.

The allergic phenotype: manifestation of 'allergic breakthrough' and imbalance in normal 'damping' of IgE antibody production.

Abstract: Antibody responses of the IgE class are, like other immxinoglobulin classes, regulated by a finely-txined network of complex cellular and molecular interactions (reviewed in Tada 1975, Ishizaka 1976, Katz 1977, 1978). The IgE system, however, has certain unique aspects to it in terms of regulatory controls for reasons that probably pertain to the biological importance of the IgE system itself. We believe, for example, that the IgE antibody system plays an important defense role against certain offending exogenous antigens, particularly those which gain access through mucoepithelial and epithelial surface linings such as the respiratory and gastrointestinal tract and skin. This defense role is performed predominantly as a consequence of the property of IgE molecules unlike other immunoglobulin molecules to bind specifically and avidly to the surface membranes of tissue-fixed mast cells and circulating basophils which express on their surfaces specific receptors for the determinants on the Fc portion of IgE. Since both of these cell types possess abundant quantities of pharmacologically-active mediators, and since their Fc receptors for IgE molecules do not discriminate such molecules on the basis of their antigen specificity, an enormous amplification mechanism exists within this system for permitting relatively small numbers of molecules to exert the desired biological effect Hence, it seems that the overall regulatory control of IgE antibody production has been tailored to

T lymphocyte stimulation by hapten-conjugated macrophages: a model system for the study of immunocompetent cell interactions.

Abstract: In previous volumes of this series (Schwartz et al. 1976, Thomas et al. 1977a) we have reviewed the structure of the major histocompatibility complex (MHC) of the guinea pig (the GPLA complex) and the critical role of I-region associated (Ia) antigens and immune response (Ir) genes in the activation of T-lymphocytes by antigen-pulsed macrophages. We have concluded that the genetic restriction of the interaction of antigen-pulsed macrophages and primed T lymphocytes appears to be regulated entirely by the histocompatibility type of the macrophage used for initial sensitization, that T cells may be specifically sensitized to antigens associated with allogeneic macrophages, and that Ia antigen expression only by macrophages is sufficient for effective interaction with T cells. We and others (Barcinski & Rosenthal 1977, Yano et al. 1977) have postulated that the site of expression of the histocompatibility-Iinked Ir genes may be at the level of the antigen presenting cell or macrophage rather than in the antigen-responsive T lymphocyte. According to this view, non-responder macrophages would lack the I-region gene product necessary to process and/or present the corresponding genetically controlled an-

Suppression of Reaginic Antibodies

Abstract: The primary as well as an ongoing IgE response to the haptens--2,4-dinitrophenyl (DNP) and benzylpénicilloyl (BPO) determinants--were readily abrogated in an immunologically specific manner by the administration of conjugates consisting of the corresponding hapten coupled to the isologous, non-immunogenic murine gamma globulins (MgammaG), i. e., DNP8-MgammaG or BPO9-MgammaG. The epitope density of the DNPx-MgammaG and BPOx-MgammaG was shown to play a dominant role in determining whether or not these conjugates were tolerogenic. Using the adoptive transfer system in mice, it was demonstrated that this method of immunosuppression was not due to the formation of suppressor cells, but involved the elimination of hapten specific IgE-forming Bepsilon cells or the inactivation of these cells through the blockade of their antigen binding receptors. This method of suppression of anti-hapten IgE antibodies, by the use of conjugates of haptens with isologous gamma-globulins, proved also effective in rats and dogs.

The influence of the major histocompatibility complex on the function of T-helper cells in antibody formation.

Abstract: The realization that MHC gene products are crucial to T-B lymphocyte cooperation came with the findings of Kindred & Shreffler (1972) and Katz et al. (1973) that histoincompatible Tand B-cells cooperate poorly if at all. Extensive studies of Katz and his colleagues using hap ten-carrier conjugates mapped the restricting genes to the I-A/I-B subregions of the mouse H-2 gene complex. Initially, this phenomenon was thought to reflect the need for interaction between like-like determinants on cooperating cells. This particular interpretation lost plausibility when it was demonstrated (von Boehmer et al., 1975, Waldman et al., 1975) that irradiated bone marrow chimeras of the type A + B ->(A X B) Fi could generate, on priming, populations of T-helper cells ol A or B origin each capable of interacting with B-cel! populations of both A and B origin {A and B are used here purely as symbols). In such 'double' chimeras the lymphoid system consists of roughly equal numbers of lymphocytes of each parental type, with very few cells of host—i. e. (A X B) F^—origin. The question now arose as to whether this apparent lack of MHC restriction reflected the elimination of allogeneic inhibitory elements from the A and B populations in the chimeras or whether selective elements in these chimeras had influenced the 'repertoire' of MHC specificities which the developing T helper cells could exploit (Katz & Benaerraf, 1976, Waldmann, 1977).

Genetic control of the immune response to Thy-1 antigens.

Abstract: CONTENTS

Restrictions Imposed on T Lymphocyte Reactivities by the Major Histocompatibility Complex: Implications for T Cell Repertoire Selection

Abstract: complete Freund's adjuvant cyclophosphamide 2, 4-dinitro-l-fIuorobenzene delayed-type hypersensitivity fowl gamma globulin terpolymer L-glutamic acidso-L-alanineso-L-tyrosineio immunoglobulin intraperitoneal ly 5-(i26i)iodo-2'-deoxyuridine . keyhole limpet hemocyanin isoenzyme B of lactic dehydrogenasc low responder ratio of radioactivity of left to right car major histocompatibility complex macrophages responders standard errors cytotoxic T cells T cells involved in DTH helper T cells suppressor T cells poly-L-(Ty r.G I u)-poly-D,L-Ala—poly-L-Lys 2, 4, 6-trinitrophenyl

Alloreactivity, the development of the T cell repertoire and the understanding of T cell function.

Abstract: CT = C57BL/6 complement constant region of immunoglobulin in heavy diain H-2D male transplantation antigen I region associated antigen immune response gene immune suppression gene H 2K keyhole limpet hemocyanin Lytl positive, Lyt23 negative T lymphocyte Lytl negative, Lyt23 positive T lymphocyte Lytl positive, Lyt23 positive T lymphocyte mixed lymphocyte reactions major bistocompatibility complex plaque forming cell sheep erythrocyte trinitrophenyl immunoglobulin variable region gene variable region of immunoglobulin heavy chin TNP p-galactosidase

Functional activity of T cells which differentiate from nude mouse precursors in a congenic or allogeneic thymus graft.

Abstract: The presence of T cell precursors in nude mice was first shown by Wortis et al. (1971) in experiments where they showed reconstitution of irradiated recipients with nude bone marrow. It was later shown that nude mice could be reconstituted with a neonatal thymus graft (Pantelouris 1971, Wortis et al. 1971) and, using the T6 chromosome as a marker, Pritchard & Micklem (1973) showed that host cells actually entered the thymus and that, 35 days after thymus grafting, all the mitotically active cells were of host origin. The use of the Thy-1 antigen as a marker made it possible to follow the repopulation of a grafted thymus in greater detail (Loor & Kindred 1973, 1974, Kindred & Loor 1975a). When a Balb/c-nu is grafted with a neonatal AKR thymus the donor and recipient T cell populations differ for the Thy-1 and TL antigens. Figure IA shows the change in the percentage of cells