Showing papers in "Immunological Reviews in 1979"

Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens.

Abstract: Xenogeneic immunizations have the advantage of detecting a wide range of antigenic determinants because many commonly occurring proteins have diverged significantly during the course of evolution and are thus antigenic in other species. The broadness of xenogeneic responses, however, means that the antisera they produce are usually complex and require extensive absorptions to make them specific for a single antigen. This problem has now been overcome by generating hybridomas producing monoclonal antibodies (Kohler & Milstein 1975). These permit dissection ofthe xenogeneic response so that large amounts of individual antibodies can be obtained, each of which recognizes only one of the determinants recognized by a broadly reactive conventional antiserum. Williams et al. (1977) used hybridoma monoclonal antibodies obtained after immunizations of mice with rat cells to study rat cell-surface antigens present on subpopulations of rat lymphocytes, i.e., differentiation antigens. Springer et al. (1978a) and Stern et al. (1978) used a similar approach to study mouse lymphocyte antigens. They prepared monoclonal antibodies by immunizing rats with mouse lymphocytes and showed that these monoclonals recognized previously undetected mouse cell surface determinants including a glycoprotein antigen that appears to be specific for macrophages (Springer et al. 1978b). Trowbridge (1978) also used rat anti-mouse immunizations to generate a monoclonal antibody against the non-polymorphic lymphocyte surface antigen T200.

Natural Killer Cells: Characteristics and Regulation of Activity

Abstract: Recently there has been increasing recognition of natural cell-mediated cytotoxicity as a potentially important antitumor effector mechanism in addition to that of specifically immune T cells and of activated macrophages. Although natural cellular cytotoxicity was first recognized only a few years ago (Herberman et al. 1973,1974, McCoy et al. 1973b, Oldham et al. 1973, Rosenberg et al. 1972,1974), there has already been extensive research in many laboratories on the nature of the effector cells, the possible mechanisms of cytotoxicity, the factors regulating the levels of reactivity, and the relevance of natural immunity to in vivo resistance against tumor growth and immune surveillance. A principal component of natural cell-mediated cytotoxicity in rodents and man has been found to be a particular subpopulation of lymphocytes which have been termed natural killer (NK) cells. We have recently reviewed in detail much of the available information on NK cells (Herberman & Holden 1978). In this paper we will only summarize our views on the characteristics of NK cells and focus on a few issues of current interest in our laboratory.

An analysis of the murine NK cell as to structure, function and biological relevance.

Abstract: The immune system in higher animals has as a major distinguishing feature a high degree of complexity. The diversified machinery in this system can be considered to represent the gradual accumulation of preserved experiences during phylogeny where primitive as well as sophisticated reactions occur in parallel during the immune response. Interactions of complicated nature are known to occur within the system and the actual effector part (s) in causing the actual rejection of, e.g. an invading organism, is frequently difficult to dissect free from other contributing factors. The cellular part of the immune system can be divided in many ways. One approach is to talk about specific cells (most people would then mean lymphocytes of B and T type that effectuate their functions via their own, antigen-specific receptors) in contrast to nonspecific cells (here often granulocytes and monocytes-macrophages are linked together). Specific cells can function via selective production of their unique antigen-

Do natural killer cells engage in regulated reactions against self to ensure homeostasis

Abstract: Host reactivities not requiring immunization in the mouse, especially natural resistance of irradiated animals to accept grafts of normal or malignant hemopoietic cells, were compared with NK activity against the YAC-1 lymphoma. The effects of several independent variables known to influence natural resistance in vivo had a similar effect on the NK system. Figure 12 lists an impressive array of shared properties and positive correlations. In contrast, the distinctions were few and minor. Many of the positive correlations were of particular significance since the experimental variables either have opposing or no effects on conventional induced immunity. The multiplicity and pervasiveness of these correlations suggest that the cellular mechanisms underlying natural reactivities are similar or common. Cytotoxic effectors mediating natural resistance to normal cells, tumors, and cells infected with intracellular pathogens may be distinct in terms of target selectivity, yet belong to a single cell lineage subject to common regulatory influences for differentiation and function. Regulation of reactivity via suppressor cells was studied in the NK system only. The spleens of mice selected for low levels of NK activity (resulting from young age, irradiation, and treatment with the macrophage-active agents l-carrageenan or hydrocortisone acetate) contained cells capable of inhibiting the lytic function of NK effectors taken from untreated adult donors. All the suppressor cells studied were thymus-independent, as judged by their occurrence in spleens of genetically athymic mice; the suppressive function was resistant to 2000 rads of gamma-rays administered in vitro and was not restricted by the major histocompatibility complex, without exception. However, two major classes of suppressors were identified: (a) macrophagelike cells inducible by l-carrageenan or hydrocortisone acetate, and (b) nonadherent cells found in spleens of untreated infants and of irradiated adult mice. It is proposed that the suppression of NK cytolysis demonstrated in vitro was a manifestation of regulatory mechanisms modulating the level of NK activity in vivo. Macrophagelike cells that are induced, activated, or inactivated by bacteria, viruses, hormones, and other agents may act as regulators of differentiation, maturation, and function of cells belonging to the NK lineage. Nonadherent cells could be either a distinct class of suppressors or immature NK cells capable of binding but not lysing target cells. In the latter case, regulation would be achieved via competitive binding of targets by pre-NK cells presumably in dynamic equilibrium with functional (i.e. matured) NK effectors.

Morphological and functional characterization of isolated effector-cells responsible for human natural killer activity to fetal fibroblasts and to cultured-cell line targets

Abstract: White cells of human blood (Oldham et al. 1973, Takasugi et al. 1973) and cells recovered from various lymphohematopoietic organs of experimental animals (Herberman et al. 1975a, Kiessling et al. 1975a) display spontaneous cytotoxic activity against various, mostly tumor, target cells in vitro. This cytotoxic activity, taking place in the absence of known presensitization, has been termed natural killer (NK) cytotoxicity. Because the natural killer phenomenon can most readily be demonstrated by using cultured tumor cells as targets, it has been suggested that the phenomenon may be linked to surveillance against cancer (Kiessling et al. 1975c, 1976a, Jondal et al. 1978). Numerous attempts have been made to characterize the effector cells responsible for the NK activity. Fractionation procedures utilizing different surface antigens, surface markers and functional properties of lymphohematopioetic cells have been employed (Herberman et al. 1975b, Kiessling et al. 1975b, Herberman et al. 1977, Kiuchi & Takasugi 1976, Jondal & Pross 1975, Vose & Moore 1977, West et al. 1977, Eremin et al. 1978, Bakacs et al. 1977,

Mechanisms of activation of human natural killer cells against tumor and virus-infected cells.

Abstract: A number of investigators have recently described specific cytotoxic effects of human lymphocytes against human target cells. For instance, in some studies cultured cell lines of tumor origin have been used as targets in attempts to demonstrate tumor-specific cell-mediated eytotoxicity (CMC) (Bubenik et al. 1971, Leventhal et al. 1972, Baldwin et al. 1973, Heilstrotn & Hellstrom 1974, O'Toole et al. 1974). Unfortunately these studies have been hampered by the fact that lymphocytes from normal donors were at least as reactive as those from cancer patients (Takasugi et al. 1973). Also, studies employing target cells infected with viruses (Steele et al. 1973, Labowskie et al. 1974, Rola-Plesczynski et al. 1975, 1976) have not produced convincing evidence for the existence of

A new approach to the study of human B lymphocyte function using an indirect plaque assay and a direct B cell activator.

Abstract: The understanding of the human immune system has been governed by technical developments. The description of electrophoresis and immunoelectrophoresis allowed the monoclonality and class specificity of myeloma proteins to be analyzed, and the recognition of agammaglobulinaemia. The description of myelomas aided development of the clonal selection theory and the variety of agammaglobulinaemias allowed speculation about lymphoid differentiation. In the humoral limb of the immune response the next major development was the discovery of B lymphocyte surface markers (Moller 1961, Coombs et al. 1969, Dickler & Kunkel 1972), which allowed characterization of B lymphocyte populations in ontogeny, immunodeficiency and leukemias (Cooper et al. 1973, Seligmann 1973). Surface markers in resting cells have proved to be poor indicators of B cell function since many agammaglobulinaemias bear a normal complement of resting B cells which are, however, unable to synthesize immunoglobulin. Functional analysis of B lymphocyte populations in murine systems has been greatly facilitated by the use of polyclonal B cell activators (PBA) to provide a nonspecific stimulus to maturation and immunoglobulin synthesis of large number of clones and by the use of the plaque assays as a sensitive technique for detection of antibody synthesis at the cellular level. Pokeweed mitogen (PWM) has been the most studied human B cell mitogen and its use has yielded valuable information in agammaglobulinaemia and in human B lymphocyte ontogeny. Activation has been assessed by morphological blast formation, cytoplasmic immunoglobulin synthesis or released immunoglobulin

Heavy chain diseases: current findings and concepts.

Abstract: Human heavy chain diseases are lymphoproliferative disorders characterized by the production of immunoglobulin molecules consisting of incomplete heavy chains devoid of light chains. Heavy chain diseases of the three main immunoglobulin classes have been described. Since the description ofthe first case by Franklin et al. (1964), close to 50 patients with gamma heavy chain disease have now been reported. The most frequent condition within the group of heavy chain diseases is a-chain disease (Seligmann et al. 1968) with more than 150 cases presently known to us. In contrast, /^-chain disease appears to be relatively rare since only 15 cases have been reported since its first description (Forte et al. 1970). Heayy chain diseases raise a number of interesting problems related to various fields such as the structure of the abnormal immunoglobulin, and the cellular genetic mechanisms responsible for the synthesis of a deleted heavy chain and, in most instances, the lack of production of light chains. In addition, the natural history and clinico-pathological patterns of these diseases may, especially in the case of a chain disease, constitute a model providing unique opportunities for research into the pathogenesis of human lymphoid malignancies.

Monoclonal antibodies to Ia antigens from rat thymus: cross reactions with mouse and human and use in purification of rat Ia glycoproteins.

Abstract: Mouse Ia antigens, rat Ia antigens (alternatively called RT-1B antigens (Howard 1978)) and human HLA-DR antigens are homologous products of the major histocompatibility complex. These antigens are highly polymorphic and have similar tissue distributions and molecular structures. In mouse, rat and man, the Ia antigen homologues are major cell surface molecules on the majority of B lymphocytes but are not found on most peripheral T lymphocytes, la antigens have also been shown to be present on some thymocytes and macrophages, spermatozoa (reviewed by Moller 1976), thymic epithelial reticular cells (Hoffman-Fezer et al. 1978) and other epithelial ceils (Wiman et al. 1978). In the mouse and rat, Ia antigens have been chemically characterized by radiochemical labeling and immunoprecipitation (Cullen et al. 1976, Silver et al. 1976, Sachs et al. 1977), while human HLA-DR antigens have been best characterized as glycoproteins purified from human B cel! lines (Snary et al. 1976, Springer et al. 1977). By either method, these antigens show similar chemical characteristics, being composed of two different glycoproteins which are non-covalently bonded but strongly associated to form a two chain structure. The smaller chain has an apparent molecular weight of approximately 25,000 to 32,000 daltons while the larger chain has an apparent molecular weight of approximately 32,000 to 36,000. Tn the mouse, it has been shown that Ia antigens with these biochemical characteristics are coded for by two loci within the major histocompatibility complex, notably in the I-A and I E / C subregions (Cullen et al. 1976).

Allograft tolerance after total lymphoid irradiation (TLI).

Abstract: The ability to induce permanent and specific transplantation tolerance in neonatal mice was first reported by Medawar and his colleagues {Medawar 1953, Billingham & Brent 1956) more than 25 years ago. Since then, several models of tolerance induction in adult laboratory animals have been developed (Binz & Wigzell 1976, Muller-Rucholtz et al. 1976, Von Boehmer et al. 1976, Yunis et ai. 1976), but as yet none have had successful clinical application. During the past several years, we developed a regimen for the induction of transplantation tolerance which allows for the permanent survival of BM, skin and heart allografts in both inbred and outbred adult animals which differ at the major histocompatibility genetic region. The tolerization regimen is based upon the use of total lymphoid irradiation (TLI), a radiotherapy technique which has been used to treat lymphoid malignancies in humans (Kaplan 1972). TLI has few severe side effects, and the mortality rate associated with this procedure is negligible (Kaplan 1972). We review here the essential features of our experimental findings, and suggest that this regimen merits further investigation with regard to applicability to clinical bone marrow and organ transplantation.

Monoclonal antibodies as tools to analyze the serological and genetic complexities of major transplantation antigens.

Abstract: The rat MHC resembles that of other species in displaying extensive polymorphism for a variety of MHC-characteristic functions: antigens detected by serological assays, antigens detected by cellular assays such as the MLR, GVH and CML, and immune response genes for a variety of cellular and non-cellular antigens (Gunther & Stark 1977, Gasser 1977). Nevertheless very little is known about the genetic structure of the region because of the shortage of laboratory recombinants. The present study grew out of the realisation that the high resolving power of monoclonal antibodies against complex polymorphic antigens could compensate for lack of resolution at the genetic level. Granted suitable monoclonal alloantibodies, the number and antigenic structure of the polymorphic molecules specified by the MHC can in principle be examined with greater precision than is possible by analysis of recombinants using planned immunizations and absorptions of conventional sera. This review describes the preparation of monoclonal antibodies by fusion of spleen cells from alloimmunized rats with mouse plasmacytoma cells and some results of an analysis of the properties of these antibodies. Some preliminary data have been published elsewhere (Galfre et al. 1977, Howard et al. 1978).

Flow Cytometry Analysis of Murine B Cell Lymphoma Differentiation

Abstract: The differentiation of lymphoid cells is a process that is fundamentally associated with the expression of all types of immune responses. Since the initial recognition of two distinct lineages of lymphoid cells in birds (Wamer et al. 1962) and mammals (Miller & Mitchell 1969, Claman & Chaperon 1969, Davies 1969), it has become increasingly evident that these two major streams of lymphocyte differentiation can become further separated into divergent pathways which lead to cells having distinctly different functional roles in the immune response. This concept has been most clearly defined in terms of T cell differentiation, in which distinct functional subpopulations of T cells mediate the different T cell activities of help, suppression, delayed sensitivity, certain alloreactivities, cytotoxicity and initiator amplifier functions (see reviews Cantor & Boyse 1976, 1977). This characterization of T cells into distinct functional subpopulations, has been shown to be associated with distinct

Human T Cell Subpopulations in Normal and Pathologic Conditions

Abstract: Thymus-derived (T) lymphocytes are by no means a homogeneous cell population. They are responsible for a spectrum of immune responses, which comprise the phenomena of cell-mediated immunity such as delayed hypersensitivity, reactivity to transplantation antigens, including mixed lymphocyte reactions and cell-mediated cytotoxicity, rejection of cell antigenically modified by malignant transformation or viral infection and cell-mediated resistance to infectious agents. In addition, T lymphocytes play a central role in regulating the functional activities of various cell populations involved in the immune responses. Among these regulatory mechanisms of particular interest is the T-B cell interaction which modulates the antibody responses of B cells in both positive (helper) and negative (suppressor) ways (Gershon 1974). During the last few years a number of experimental observations in mice allowed to attribute these properties to distinct subclasses of T lymphocytes identified mainly by different surface alloantigens. The most promising marker for the identification of functional subsets of T cells has been the Ly antigen system. Thus, T cells bearing Ly 1 alloantigen show a helper activity in both the antibody response, and in the generation of cytotoxic T lymphocytes (CTL) respond to determinants coded for by the I and S regions in mixed lymphocyte reactions (MLR) and are the effector cells in delayed-type hypersensitivity reactions. Ly 2 and 3 alloantigens are present on suppressor T cells and on CTL, respond in MLR by recognizing K and D region differences on the allogeneic target cells (Cantor & Boyse 1975 a, b, 1977, Huber et al. 1976).

Differentiation capacity and other properties of the leukemic cells of chronic lymphocytic leukemia.

Abstract: It is well established that chronic lymphocytic leukemia (CLL) in man is a clonal proliferation of B cells. In the majority of cases, the leukemic lymphocytes bear IgM and IgD as their surface immunoglobulins(Ig)(Fuet al. 1974a, Kuboetal. 1974, Preud'homme et al. 1974). Despite a number of differences from normal B cells, these homogeneous B cell populations have been helpful in the studies of human B lymphocytes. In this laboratory they have facilitated the analysis of the orientation of surface IgM and IgD and the possible sites of membrane insertion of these molecules (Fu & Kunkel 1974). They also have helped in the demonstration and characterization of the presence of la-like molecules on human B lymphocytes (Winchester et al. 1975). Recently, a small group of CLL cases in which a monoclonal serum Ig protein is present in addition to marked lymphocytosis have proven of special interest. In some of these cases, a direct relationship between the leukemic lymphocytes and the serum monoclonal protein has been documented by idiotypic analysis involving the serum Ig band and the surface Ig on the leukemic cells (Fu et al. 1974b, Salsano et al. 1974, Hurley et al. 1978). The availability of the idiotypic determinant as a leukemic specific marker and a clone of B cells at different stages of maturation, spanning from lymphocytes to plasma cells, has proven very useful. In this review primary emphasis will be placed on studies involving the differentiation of leukemic B cells to plasma cells. Analyses of these leukemic cells have provided considerable information directly applicable to normal B cells. In addition, certain functional and structural abnormalities of these leukemic B cells will also be discussed.

Bcl1, a murine model for chronic lymphocytic leukemia: use of the surface immunoglobulin idiotype for the detection and treatment of tumor.

Abstract: B cell neoplasms account for a significant proportion of human lymphoid tumors and also represent major problems in management (Lennert & Mohri 1978). About 75% of non-Hodgkins lymphomas and virtually all chronic lymphocytic leukemias (CLL) are of B cell origin. Treatment of B cell lymphomas is generally unsatisfactory and prediction of the clinical course based on the histology of tumors is unreliable. With regard to CLL, although many patients have a benign disease and essentially live a normal life span, others have a more malignant form of the disease and despite chemotherapy have a very shortened life span after diagnosis. Because of the extensive information concerning murine immunology and immunogenetics and the availability of inbred congenic mouse strains, murine tumors offer major experimental opportunities. Until recently,, virtually all leukemias and lymphomas described in the mouse were of T cell origin, despite the prevalence of spontaneous and induced myelomas in this species (Potter 1976). However, during the last decade, a number of B cell lymphomas, both spontaneous and induced, have been described. Thus. Abelson virus infection in murine bone marrow or spleen gives rise to permanently growing neoplastic cell lines with the features of pre-B or very immature B cells (Abelson & Rabstein 1970, Premkumar et al. 1975, Boss et al. 1979). Two chemically induced prc-B

Murine Monoclonal Antibodies against HLA Structures

Abstract: The specificity of antibodies, encoded in their combining sites, is complementary to determinant groups of the immunogen. These determinants are tridimensional fractions of a larger structure. Moreover the immune system of the immunized animal is able to respond with a variety of different antibodies against the same immune determinant, the main limit to this freedom being the similarity between the determinant in question and some structures of the animal's tissues, for which a state of tolerance normally exists. Thus, when an animal is injected even with a relatively simple antigen, the antibody population against the immunogen is usually highly dishomogenous. While the complexity of the antibody response has an obvious selective advantage as a mechanism of defense, it greatly limits the resolving power of "antisera" as analytical tools for the recognition of different antigens and for the topographic description of the molecules involved. Carbonara et al. (1969) were among the firsts to prove that the heterogeneity of the antibody response has its basis in the polyclonality of activated immunocytes, which is reflected in the compartimentalization of the responding organ. By dissecting the spleen or draining lymph nodes of the immunized animal into small fragments, Luzzati et al. (1970) obtained the in vitro synthesis of antibodies with the characteristics of monoclonality. The antibody-secreting hybridoma k la Kohler-Milstein (1975), has major merits for immune analysis: the antibody is produced in vitro in unlimited large amounts and at high titers. It has well defined characteristics which remain constant in the course of time. Chiefly, hybridoma antibodies can be reduced to a strictly homogenous population of identical Ig molecules, when the primary culture has been cloned.

Murine models of tolerance induction in developing and mature B cells.

Abstract: Subsequent to the classic studies on immunologic tolerance by Medawar (1956), Burnet (1959) perceived that tolerance to self-antigenic determinants occurred during the ontogenetic development of the individual. He proposed that during the development of immunocompetence, clones reactive to autologous antigens were deleted after contact of these antigens with the reactive cells' specific antigen receptors. However, as the participation of both B cells and T cells in immune responsiveness became apparent (Claman et al. 1966, Mitchison 1967, Miller & Mitchell 1968, Taylor 1969, Mitchison 1971), it was not clear whether the observed unresponsiveness to self-determinants involved T cells or B cells (Taylor 1969. Gershon & Kondo 1971, Weigle et al. 1971, Weigle 1973, Basten et al. 1974). In order to examine the role of B cells in the development of unresponsiveness to self-antigens, several murine models of B-cell tolerance have been developed. Until recently, these studies have been generally restricted to analyses of adult responses (Weigle 1973, Howard & Mitchison 1975), since responses by neonatal cells and the necessary controlled comparisons of neonatal and adult cells have been technically difficult to achieve. Furthermore, interpretation of adult responses in B-cell tolerance models has been complicated by the attempts to

Immunosuppression for organ grafting -- observations on cyclosporin A.

Abstract: The gulf between clinical organ grafting and basic immunology has always been wide. Satisfactory organ grafting models in the laboratory that can be directly transferred to the clinic do not exist. Clinicians have used empirical treatment to obtain therapeutic effects for more than 15 years since the introduction of an immunosuppressive regimen of Azathioprine and corticosteroids. Schwartz & Damashek (1959) showed that treatment of rabbits with 6-mercaptopurine for 2 weeks prevented the production of antibodies against foreign protein injected at the commencement of treatment and the effect persisted beyond the period of treatment and was specific for the antigen given at the time of the drug. Although the results were variable and the drug toxic, 6-mercaptopurine also impaired the rejection of kidneys grafted between unrelated mongrel dogs (Calne 1960, Zukoski et al. 1960). A variety of thiopurines were investigated and Azathioprine was found to be most effective in the canine renal graft model (Calne 1961). Goodwin et al. (1962) reported prolongation of kidney allograft survival in patients treated with steroids. The combination of Azathioprine and steroids was adopted in clinical practice and resulted in the first therapeutically valuable kidney grafts. Now more than 30,000 kidneys have been transplanted, yet despite the introduction of numerous adjuncts to this basic immunosuppressive regimen results have changed little in the last 10 years. Renal allografts between siblings identical for the A and B MHC antigens have excellent long term survival. Although occasionally there is acute rejection, the outcome of these grafts is nearly as good as grafts between identical twins. Matching for the A and B loci has less prognostic significance in grafts from unrelated donors, but avoiding a positive cross-match in recipients

Multiple Pathways of B Lymphocyte Tolerance

Abstract: ABC = antigen-binding cells FL = fluorescein hapten FL-gcl = fluoresceinated-gelatin HGG = human gamma globulin HMS = hapten modified self KLH = keyhole limpet hemocyanin LPS = iipopolysaccharlde from Escherichia coli 055: B5 MGG = isologous mouse IgG PBA = polyclonal B cell activators PFC = plaque-forming cells POL = po\\ymenzQdnagelVm ^romSalnonellaadelaidesvj 1338 RBC = red blood cells SGG = sheepgamma globulins TD = thymus-derived cell dependent TI = thymus-derived cell independent TNBS ~ trinitrobenzene sulfonic acid TNP = trinitrophenyl hapten TNP-SC = trinitrophenylated syngeneic spleen cells

Functional subsets of murine and human b lymphocyte cell lines.

Abstract: Although human B-cell lines have been described since 1964 (Pulvertaft 1964, Epstein & Barr J964), having easily detectable immunoglobulin (Tanigaki et al. 1966), similar murine lines have become available only in the past 2 years. The purpose of this review is to demonstrate that murine and human B-cell lines can be categorized into groups with respect to responsiveness to B-lymphocyte mitogens and other agents, and to suggest relationships between these subsets and the stages of normal B-lymphocyte development.

Properties of rat anti-MHC antibodies produced by cloned rat mouse hybridomas

Abstract: INTRODUCTION The major histocompatibility complex (MHC) is a large and highly polymorphic collection of genes found in virtually every vertebrate organism possessing an identifiable immune response (Burnet 1968, Hildemann et al. 1979). Indeed, the function of the MHC appears to be intimately involved with the immune system in a variety of ways (Jerne 1970). For example, in the mouse, K and D regions of the H-2 complex act as restriction elements for both viral-specific killer T cells (Doherty et al. 1976) and most allogeneic killer T cells (Nabholz et al. 1974, Forman & Moller 1974). Genes within the I region encode for products which govern overall response to certain antigens (Benacerraf & Germain 1978) and serve as restriction elements for cell-cell cooperation in some immune responses (Niederhuber 1978). I region antigens are recognized as the primary stimulus by allogeneic T ceils in the proliferative phases of the mixed leukocyte culture (MLC) (Bach et al. 1977) and encode for certain T ceil factors capable of suppressing immune responses (Tada et al. 1977). Because of the central importance of the MHC gene complex in multiple immunological processes, it seems obvious that better definition of the gene products of this region could contribute substantially to our understanding of the biological function of the MHC. The demonstration by Kohler & Milstein (1975) that it is possible to

Immunogenetic analysis of "natural killer" activity in the mouse.

Abstract: The lymphocyte population of the mouse may be viewed as a self-contained network of functionally distinct sets that continuously communicate with each other. The genetic program of each set of cells combines information coding for a unique set of cell-surface glycoproteins (which can be defined by specific antisera) and a particular physiologic function (Cantor & Boyse 1977a). Immunogenetic analysis of several types of immunologic responses has indicated an additional point: the immunologic function of each lymphocyte set is precisely and specifically regulated by the activity of other lymphocyte sets (Cantor & Boyse 1977b, Eardley et al. 1978, Cantor et al. 1978, Cantor & Gershon 1978). In many ways the immune system is analogous to other complex systems of cellular communication in higher organisms: each is regulated mainly by signals generated from within the system itself. One example of the use of immunogenetics to analyze a lymphocyte set is the definition of cells responsible for the so-called natural killer (\"NK\") phenomenon. This term refers to the observation that spleen cells from nonimmune mice (or blood lymphocytes from people) can lyse or damage a variety of target cells, notably malignant cells, in vitro (Greenberg & Playfair 1974, Kiessling et al. 1975a, 1975b, Herberman etal. 1975a, 1975b, Sendo etal. 1975). This activity is independent of antibody and complement and does not reflect conventional phagocytic activity. Cells responsible for this reaction are said to resemble small lymphocytes morphologically, and are found mainly in spleens of young animals. Although their numbers and activity may be raised in pathologic states (Glimcher et al. 1977) and by diverse agents such as interferon (Gidlund et al. 1978) and certain immunopotentiators (Wolfe et al. 1976), their activity is

Regulation of B cell activity in man: role of T cells.

Abstract: Abbreviations: AC adherent cells cig cytoplasmic immunoglobulin(s) FcyR membrane receptor for the Fc-fragment of IgG ¥cfiR. membrane receptor for the Fc-fragment of IgM He haemocyanine Helix pomatia OA ovalbumin OA-DNP12-11 ovalbumin conjugated with the hapten DNP (ratio 1 to 12-15) PBL peripheral blood lymphocytes PFC plaque-forming cell PNP purine nucleoside phosphorylase PWM pokeweed mitogen SCID severe combined immune deficiency SE sheep erythrocytes TDL tonsil-derived lymphocytes Th T heiper (cell or cells) ThFw T helper factor originating from antigen-stimulated T cells stimulated for 24 h ThFiio T helper factor originating from antigen-stimulated T cells stimulated for 120 h Ts T suppressor (cell or cells) TSB, T suppressor activator cell Tscff T suppressor effector cell TSF24 T suppressor factor originating from antigen-stimulated T cells cultured for 24 h TsFijo T suppressor factor originatingfromantigen-stimuIatedTceUscuUuredforl20h TSpr. T suppressor precursor cell Ty cell T lymphocyte expressing FcyR T^ cell T lymphocyte expressing Fc^R To T lymphocyte without demonstrable Fc/iR and FcyR

Transformation of Immature Lymphoid Cells by Abelson Murine Leukemia Virus

Abstract: Leukemia viruses have a special interest for Immunologists because many of them transform cells of the lymphocyte lineage into contitiuously growing permanent lines of cells. One of the most useful of such viruses is the Abelson murine leukemia virus (A-MuLV) (Rosenberg & Baltimore 1979). This virus is able to generate lines of cells with properties that suggest the cells are counterparts of various stages of B-lymphocyte differentiation. The ability of a virus to transform a specific lineage of cells raises a wide range ofquestions. These questions include: What genetic elements of the virus play a role in Its transformation ability? What proteins are made by the virus that play a role in transformation? How do these proteins work? What kind of cell is a target for the virus? What characteristics can be used to define the differentiation state of the resulting tumor cells? Can such tumor cells be used to understand the normal process of differentiation? In this review we will attempt to summarize the present state of knowledge about these various questions in relation to A-MuLV and suggest the types of information that may be derived from future studies. A-MuLV came to light during an experiment in which Abelson & Rabstein (1970 a,b) infected steroid-treated BALB/cCr mice with Moloney murine leukemia virus (M-MuLV) (Fig. 1). One of the mice in the study developed a lymphosarcoma 37 days after virus infection. This tumor involved the cervical and inguinal lymph nodes, the lower vertebral column, the marrow of the calvaria and the meninges. No evidence of a thymic tumor was present. Histologically, the tumor cells were indistinguishable from other virus-induced lymphoma cells. The lymphoblasticcells were oflarge size with a high nucleus to cytoplasm ratio. The nucleus was characterized by diffuse chromatin and a prominent nucleolus and the cytoplasm had abundant free ribosomes (Rabstein etal. 1971, Siegler etal. 1972).

Human B cell function in a polyclonally induced plaque forming cell system. Cell triggering and immunoregulation.

Abstract: The use of a sensitive PFC assay against a specific antigenic determinant (SRBC) following polyclonal triggering of human lymphocytes has provided a unique insight into the complex mechanisms of triggering of human B cells. The system is under the strict regulation of a delicate balance between helper and suppressor influences reflecting in certain circumstances the activity of distinct subsets of immunoregulatory cells. Lymphoid cells in certain diseases characterized by disordered immunoregulation, when as system, may in effect be manifesting an abnormal expression of immunoregulatory mechanisms operable in normal immune responses. In vivo activation of lymphoid cells by PBAs may have an important role in disease states as well as in the subsequent in vitro expression of B cell function. Furthermore, it is quite possible that under certain circumstances some B cell responses which appear to be purely antigen-specific may be reflections of synergy between PBA substances and specific antigen. The use of PBAs as probes and sensitive PVC systems as assays has already proven fruitful in the dissection of the complex mechanisms of nonspecific B cell triggering in man and may indeed ultimately lead to an understanding of the mechanisms of specificity of immune reactivity.

Neonatal tolerance: towards an immunogenetic definition of self.

Abstract: Within the universe of antigens there exists a particular subset of molecules that are regarded by the immune system of a single individual as unique because they represent the molecular determinants of 'Self. During the normal course of events. Self determinants expressed on normal tissues do not evoke a specific, destructive auto-immune response, whether cellular or humoral. By contrast, virtually all other molecules included in the antigenic universe are perceived as NonSelf by the immune system; their introduction into an adult organism evokes a highly specific effector response. Appreciation of the inherent conservativism and unity of biologic systems makes it apparent that there must be no fundamental physicochemical differences that distinguish Self from NonSelf molecules. Rather, the obvious disparity with which the immune system responds to Self and NonSelf must reside at the level of the immune system itself. Understanding the process by which Self tolerance is achieved remains the central issue in contemporary immunology.