Showing papers on "Immune system published in 1971"

The somatic generation of immune recognition.

Abstract: Antibody specificity is determined by structural v-genes that code for the amino acid sequences of the variable regions of antibody polypeptide chains. The present hypothesis proposes that the germ-cells of an animal carry a set of v-genes determining the combining sites of antibodies directed against a complete set of a certain class of histocompatibility antigens of the species to which this animal belongs. The evolutionary development of this set of v-genes in phylogeny is traced back to the requirements for cell to cell recognition in all metazoa. The hypothesis leads to a distinction between two populations of antigen-sensitive cells. One population consists of cells forming antibodies against foreign antigens; these lymphocytes have arisen as mutants in clones descending from lymphocytic stem cells which expressed v-genes belonging to the subset (subset S) coding for antibody against histocompatibility antigens that the individual happens to possess. The other population consists of allograft rejecting lymphocytes that express v-genes of the remaining subset (subset A) coding for antibody against histocompatibility antigens of the species that the individual does not possess. The primary lymphoid organs are viewed as mutant-breeding organs. In these organs (e. g. in the thymus), the proliferation of lymphocytes expressing the v-genes of subset S and the subsequent suppression of the cells of these “forbidden” clones, leads to the selection of mutant cells expressing v-genes that have been modified by spontaneous random somatic mutation. This process generates self-tolerance as well as a diverse population of antigen-sensitive cells that reflects antibody diversity. The proliferation in the primary lymphoid organs of lymphocytes expressing v-genes of subset A generates the antigen-sensitive cell population that is responsible for allo-aggression. The theory explains how a functional immune system can develop through a selection pressure exerted by self-antigens, starting during a period in early ontogeny that precedes clonal selection by foreign antigens. The hypothesis provides explanations for the variability of the N-terminal regions of antibody polypeptide chains, for the dominant genetic control of specific immune responsiveness by histocompatibility alleles, for the relative preponderance of antigen-sensitive cells directed against allogeneic histocompatibility antigens, for antibody-idiotypes, for allelic exclusion, for the precommitment of any given antigen-sensitive lymphocyte to form antibodies of only one molecular species and for the cellular dynamics in the primary lymphoid tissues.

Suggestive evidence that the "blocking antibodies" of tumor-bearing individuals may be antigen--antibody complexes

Abstract: Sera from mice carrying progressively growing sarcomas induced by Moloney virus or methylcholanthrene can block the cytotoxic effect of lymphocytes immune to the tumor-specific antigens of the respective neoplasms. The blocking effect can be specifically removed by absorbing sera with the respective types of tumor cells, and it can be recovered from these cells by elution at low pH. If the low pH is maintained, it is possible to separate out a low and a high molecular weight fraction from the eluates. If the fractions are added to the target cells for 45 minutes and then removed, neither of these fractions can block lymphocyte-mediated cytotoxicity, while a 1:1 mixture of them has a specific blocking effect. If they are admixed with the lymphocytes, incubated for 1 hr, and then allowed to incubate with the target cells and lymphocytes during the entire 2 days of the test, the low molecular weight fraction, as well as the mixture, but not the high molecular weight fraction, has a blocking activity. It is suggested that the blocking factor in sera from tumor-bearing animals, as regularly tested, is an antigen-antibody complex, capable of binding to the target cells and/or reacting with lymphocytes immune to their antigens, thus blocking the lymphocytes' reactivity; the latter reaction is postulated to be of a temporary nature.

The carrier effect in the secondary response to hapten-protein conjugates. II. Cellular cooperation.

Abstract: The adoptive secondary response of mice to conjugates of NIP (4-hydroxy-5-iodo-3-nitro-phenacetyl-) and DNP (2,4-dinitrophenyl-) is here used to elucidate the mechanism of cellular cooperation. The framework into which the experiments fit can be formulated as follows. Priming immunization raises a crop not only of specific antibody-forming-cell-precursors (AFCP) but also of specific helper cells. Upon secondary stimulation the helper cells serve a role as handlers or concentrators of antigen, thus enabling AFCP which would otherwise be incapable of reacting to initiate antibody synthesis. In this act of cooperation both cells recognise antigen; in the system examined here the helpers recognise carrier determinants and the AFCP recognise either the hapten or other carrier determinants. The first aim of the experiments was to raise populations of helpers and AFCP of distinguishable specificity. Mice were primed with NIP-Ovalbumin (OA) mixed with chicken γ-globulin (CGG) and bovine serum albumin (BSA); in comparison with controls primed with unmixed NIP-OA, their cells after transfer were relatively more sensitive to secondary stimulation with NIP-CGG or NIP-BSA and similar findings were obtained in cross-checks of these carriers. For reasons which are not entirely clear, non-transferred cells did not show the same effect. In further experiments cells primed with one conjugate (e. g. NIP-OA) were mixed with cells primed with another protein (e. g. BSA), transferred and challenged with the hapten conjugated to the second protein (i. e. NIP-BSA). In comparison with controls lacking the protein-primed cells, the mixture regularly showed greater sensitivity to stimulation. NIP and DNP were tested in many of the possible combinations with BSA, OA and CGG with the same result. The mixture system was used in the further analysis. Tests with allotype-marked protein-primed cells showed that these cells did not participate in the production of the anti-hapten antibody and could therefore properly be regarded as helpers. Tests of specificity showed that physical union of the hapten and carrier were required: cells primed with BSA, for example, would not help NIP-OA-primed cells to make a response to NIP-HSA even when stimulated at the same time with BSA. Transfer of less than one-tenth of the spleen gives a maximum helper effect, whereas AFCP activity continues to rise as larger numbers of cells are transferred. Helper cells are therefore normally present in excess. Helper activity is more resistant than AFCP activity to irradiation, drugs and semi-allogeneic cell transfer across an H-2 barrier. This suggests that helper cells play a relatively passive role in the immune response. Several observations indicate that helper cells are thymus-derived mediators of cellular immunity. Passively transferred antibody did not substitute for helper cells. After immunization helper activity developed faster than AFCP activity. Spleen cells obtained from lethally-irradiated, thymocyte-repopulated, immunized donors provided help. Cells from the thymus-derived fraction of thymus/marrow chimeras also appear to provide help. Thus, the hapten-carrier cooperative response maps onto the well-established synergy of thymus and marrow in the response to foreign erythrocytes.

Systemic lupus erythematosus: prototype of immune complex nephritis in man

Abstract: Serological studies, immunofluorescence studies, and immunochemical assays of glomerular eluates indicate that several antigen-antibody systems may be involved in the pathogenesis of the tissue lesions of SLE. The NDNA-anti-NDNA system appears to be operative in most patients with active SLE. In addition, antibodies to SDNA are found with considerable frequency in SLE sera and glomerular eluates. It is not known if these antibodies fix to NDNA which has been denatured after deposition in glomeruli or if SDNA-anti-DNA complexes are deposited initially. NDNA antigen has been demonstrated in both serum and glomerular deposits, and SDNA determinants have also been found in glomerular deposits. In addition, there is evidence that rheumatoid factor contributes to the immune complex deposition in certain patients either by fixing to preformed immune complexes or as part of an independent gamma-globulin-anti-gamma-globulin system. It is anticipated that the definition of these immune systems, and the assessment of their relative toxicity will provide insight into underlying etiologic factors as well as provide a sound basis for therapy in this form of glomerulonephritis.

The relationship between antigenic structure and the requirement for thymus-derived cells in the immune response

Abstract: Certain antigens such as polymerized flagellin are capable of producing relatively normal antibody levels in thymectomized mice, whereas others, including heterologous erythrocytes require the presence of T cells in a helper capacity. The mechanism of thymus-independent antibody production was investigated by comparing the primary IgM responses of spleen cells from ATXBM, XBM, and normal mice to various physical forms of the flagellar antigens of Salmonella adelaide in vitro. No reduction in antibody-forming cell levels to polymerized flagellin over a wide dose range was observed in ATXBM cultures, although the same spleen cells did not respond to an optimal dose of sheep red cells. In contrast, when flagellar determinants were presented in a monomeric form or as flagellin-coated donkey red cells, a highly significant difference was observed between the antibody responses of spleen cells from ATXBM mice and XBM or normal controls. The results suggested that the requirement for T cells in antibody production is not a property of specific antigenic determinants, but depends on the mode of antigenic presentation. The validity of this conclusion was confirmed by using another antigenic determinant (DNP) coupled either to the thymus-independent carrier, POL, or to the thymus-dependent carrier, DRC. Spleen cells from XBM mice produced comparable AFC levels to both forms of DNP, but the results from ATXBM cultures showed a marked difference. The anti-DNP response to DNP-DRC was greatly reduced compared to controls, whereas that to DNP-POL was normal even after prolonged thoracic duct drainage of the ATXBM donors and pretreatment of their spleen cells with anti-θ-serum and complement. The data presented here imply that the role of T cells in humoral immunity is the presentation of antigen to B cells in such a manner as to initiate optimal antibody synthesis.

Interaction of cells with immune complexes: adherence, release of constituents, and tissue injury

Abstract: Neutrophils are essential mediators of tissue damage in many forms of immune complex-induced injury. In vitro, they have been shown to release some of their content of injurious constituents upon reaction with immune complexes (Fig. 10). If the complexes are distributed along a nonphagocytosable surface, degranulation to the exterior of the cell is observed. When the complexes were phagocytized, however, degranulation into the phagocytic vacuole, and some loss of enzymes into the surrounding medium, occurred. This may have resulted from a momentary opening of the vacuole to allow ingestion of additional particles, as was demonstrated with the electron microscope. This phenomenon was particularly noticeable when the particles were relatively large. Far more immune complex is required to induce release when in a phagocytosable form than when on a nonphagocytosable membrane. Neutrophils may be attracted to sites of immune complex deposition in many parts of the body (arteries, heart, skin, brain, kidney, joints) by complement-mediated processes. In some situations, e.g. in the joint fluid, they would encounter free immune complexes, phagocytose them, and release enzymes. In many others, in which immune complexes may be distributed along surfaces, such as in the glomerulus, adherence of neutrophils may also lead to release of injurious constituents (proteases, collagenase, elastase, permeability factors) capable of digesting and injuring the tissues.

Effect of prostaglandin E 1 on adjuvant arthritis.

Abstract: WE have found that when rats are treated with the prostaglandin PGE1 adjuvant arthritis is prevented and suppressed. Although the treatment had no effect on delayed hypersensitivity to PPD, it reduced the immune response to sheep red blood cells (SRBC). Our findings support earlier indications that PGE1 might modify the inflammatory response1,2.

Requirement of thymus-dependent lymphocytes for potentiation by adjuvants of antibody formation.

Abstract: THE mode of action of immunological adjuvants is of theoretical as well as practical importance. Adjuvants can not only increase immune responses; they can also bring about change from one type of immune response to another. For example, doses of bovine serum albumin (BSA) that in the absence of adjuvant induce tolerance, in the presence of adjuvants induce antibody formation1,2. To understand how adjuvants switch on antibody formation it may be necessary to determine which of the cells involved in the immune response are affected by adjuvants. Earlier experiments3–5 led to the conclusion that the cells initially involved in the action of adjuvants are macrophages. This interpretation was based on observations that particulate adjuvants (such as bacteria) are ingested by macrophages but not by lymphocytes. Non-particulate or particulate adjuvants taken up by macrophages in culture and injected into syngeneic mice increased the antibody response of the recipients to two proteins (Maia squinada haemocyanin or bovine serum albumin (BSA)); in contrast, adjuvants taken up by lymphoid cells used to reconstitute immune responses in irradiated recipients had no demonstrable effect on antibody formation.

Immune response to chemically modified flagellin. II. Evidence for a fundamental relationship between humoral and cell-mediated immunity.

Abstract: Flagellin (mol.wt. 40,000) from S. adelaide organisms and a series of acetoacetyl derivatives of flagellin were tested for their ability to induce humoral and cell-mediated immunity in adult rats. It was found that unmodified flagellin was an excellent inducer of antibody formation but a poor inducer of delayed-type hypersensitivity. In contrast, increasing acetoacetylation steadily destroyed the ability of flagellin to initiate antibody formation but enhanced the capacity of the molecule to induce flagellin-specific cell-mediated immunity and antibody tolerance. In fact, it appeared that in adult rats antibody formation and cell-mediated immunity may well be opposing immunological processes. Furthermore, the affinity of the acetoacetyl flagellins for anti-flagellin antibodies appeared to determine the type of immune response which predominated. High affinity antigen produced antibody formation whereas low affinity antigen induced cell-mediated immunity and antibody tolerance. The importance of affinity was further evidenced by the fact that a CNBr digest of flagellin induced humoral and cellular immune responses identical to an acetoacetylated flagellin of comparable antigenic activity. From these studies it was proposed that both humoral and cell-mediated immunity can be directed against the same antigenic determinants but that the specificity requirements for delayed hypersensitivity (and antibody tolerance) are less than those required for antibody formation. Some remarkable immunological features of the flagellin system were revealed. Flagellin induced comparable delayed-type hypersensitivity when injected in either saline or FCA. Furthermore, FCA only slightly enhanced the delayed responses induced by the acetoacetyl flagellins and in fact these preparations produced antibody tolerance whether injected in saline or adjuvant. Finally, in contrast to the adult tolerance induced by the acetoacetylated flagellins, which existed only at the antibody level, tolerance in neonatal rats existed at the level of both humoral and cell-mediated immunity. This finding is the first indication of a fundamental difference between neonatal and adult tolerance. The significance of these findings is discussed in the light of current immunological concepts and a hypothesis proposed to explain these phenomena.

Mechanisms involved in the deposition of immune complexes in tissues.

Abstract: The mechanisms reponsible for the deposition of circulating immune complexes have been analyzed. An active process appears to be responsible in both a laboratory model in guinea pigs and in acute immune complex disease (serum sickness) in rabbits. In rabbits, after the injection of antigen to induce serum sickness, immune complexes appear in the circulation. In addition, homocytotropic (IgE) antibody is formed which binds to the surface of basophils. Leukocyte suspensions containing these basophils, when combined with specific antigen, release a soluble factor that causes clumping of platelets and release of their vasoactive amines. An excellent correlation was found between the presence of this mechanism of release of vasoactive amine and the deposition of immune complexes in serum sickness of rabbits. Antagonists of vasoactive amines or depletion of platelets, the major circulating reservoir of these amines, suppressed the deposition of circulating immune complexes and inhibited glomerulitis and arteritis. Upon entering the walls of vessels, the complexes became lodged immune complexes, greater than 19S in size, were deposited along the membranes. The data suggest that at a time when immune complexes appear in the circulation of an immunized rabbit, vasoactive amines are released from platelets in areas where turbulence of blood occurs. Sensitized basophils participate in the release of vasoactive amines from the platelets. The amines induced increased vascular permeability which leads to deposition of large complexes from the circulation in vessel walls by a process of filtration. The deposited complexes then induce inflammatory injury.

Cellular immunity in vitro : i. immunologically mediated enhancement of macrophage bactericidal capacity

Abstract: An in vitro model of cellular immunity in the guinea pig was established. Animals were immunized with tubercle bacilli, bovine gamma globulin, or picrylated human serum albumin in complete Freund's adjuvant. Oil-induced peritoneal exudates from immune and control animals were cultured overnight with and without specific antigen. The cultures were washed and the macrophage monolayers were infected with Listeria monocytogenes. At intervals the monolayers were lysed and the numbers of viable intracellular bacteria were quantitated by pour plate cultures. Random monolayers were also evaluated in sequence by visually counting the intracellular bacteria on Gram-stained plates. Both methods demonstrated that the macrophages from immune animals had markedly enhanced listericidal activity when the peritoneal exudates were cultured with antigen before infection. Macrophage migration inhibition was also demonstrated under these conditions. The experiments reported here describe an in vitro model of cellular immunity which will allow separation and recombination of cell types and direct assay of cell products in efforts to elucidate further the mechanisms of the immunologically mediated enhancement of macrophage bactericidal capacity.

Cell-to-cell interaction in the immune response vi. contribution of thymus-derived cells and antibody-forming cell precursors to immunological memory

Abstract: Collaboration between thymus-derived lymphocytes and nonthymus-derived antibody-forming cell precursors occurs in the primary antibody response of mice to heterologous erythrocytes and serum proteins. The purpose of the experiments reported here was to determine whether collaboration took place in an adoptive secondary antibody response. A chimeric population of lymphocytes was produced by reconstituting neonatally thymectomized CBA mice soon after birth with (CBA x C57BL)F(1) thymus lymphocytes. These mice could be effectively primed to fowl immunoglobulin G (FgammaG) and their thoracic duct lymphocytes adoptively transferred memory responses to irradiated mice. The activity of these cells was impaired markedly by preincubation with CBA anti-C57BL serum and to a lesser extent by anti-theta-serum. Reversal of this deficiency was obtained by adding T cells in the form of thoracic duct cells from normal CBA mice. Cells from FgammaG-primed mice were at least 10 times as effective as cells from normal mice or from CBA mice primed to horse erythrocytes. These results were considered to support the concept that memory resides in the T cell population and that collaboration between T and B cells is necessary for an optimal secondary antibody response. Poor antibody responses were obtained in irradiated mice given mixtures of thoracic duct cells from primed mice and of B cells from unprimed mice (in the form of spleen or thoracic duct cells from thymectomized donors). In contrast to the situation with T cells, the deficiency in the B cell population could not be reversed by adding B cells from unprimed mice. It was considered that memory resides in B cells as well as in T cells and that priming probably entails a change in the B cell population which is fundamentally different from that produced in the T cell population.

Mechanisms of recovery from a generalized viral infection: mousepox iii. regression of infectious foci

Abstract: Histological and immunofluorescence techniques showed that mononuclear cells invaded virus-infected foci in the livers of passively immunized mice within 10 hr of the receipt of immune spleen cells or hyperimmune serum; by 24 hr, marked destruction of virus antigens had occurred in these lesions. Immune cell transfer promoted denser packing of mononuclear cells in the foci and more efficient destruction of infectious material than immune serum. Similar liver lesions developed by the 6th day after sublethal, primary, subcutaneous infection in normal mice. In contrast, in mice with GVHR which were immunosuppressed but possessed hyperactive macrophages and unimpaired splenic interferon response, mononuclear cells did not invade liver lesions and the animals died. These results, together with data reported previously, indicated that mononuclear cell invasion of infected liver foci, triggered by CMI, was of key importance in recovery from primary mousepox. The roles of specifically sensitized lymphocytes and macrophages within lesions were not directly evaluated, but indirect evidence suggested that lymphocytes could cause no more than a halt in virus multiplication, and that macrophages were required for the inactivation of preformed virions. Possible augmentation of the efficiency of macrophages by locally-produced lymphocyte interferon, neutralizing antibody, or stimulation of their phagocytic and intracellular digestive capacity cannot be excluded.

In vitro and in vivo activity of a lymphocyte and immune complex-dependent chemotactic factor for eosinophils.

Abstract: When cultured in the presence of specific antigen, lymphocytes from delayed-hypersensitive guinea pigs release a number of biologically active substances into the culture medium. Such active supernatants can react with immune complexes in vitro to generate a factor which is chemotactic for eosinophils. The factor involved is unique, since previously described chemotactic factors for other cell types require for their generation either immune complexes or substances released into lymphocyte culture, but not both. In the case of the eosinophil chemotactic factor, the interaction between the substance elaborated by the lymphocytes and the immune complexes appears to be specific in that the immune complexes must contain the same antigen as that used to activate the lymphocyte cultures. Although this factor was generated in an in vitro system, it has been shown to possess in vivo as well as in vitro activity. It is therefore possible that this factor may be of biological significance in situations where eosinophils are participants in inflammatory or immunologic reactions.

Mechanisms of recovery from a generalized viral infection: mousepox. II. Passive transfer of recovery mechanisms with immune lymphoid cells.

Abstract: The following passive transfer experiments evaluated the contributions of the various host responses in recovery from mousepox. (a) Immune spleen cells transferred highly efficient antiviral activity, but preinfected recipients of these cells made no detectable splenic interferon or antibody in the 24 hr interval after cell transfer. (b) Passively administered interferon was ineffective. (c) Recipients of hyperimmune serum had much more antibody than recipients of immune spleen cells but significantly less antiviral activity. (d) Immune spleen cell populations with antiviral activity contained mediators of CMI to virus antigens. (e) The antiviral activity of immune spleen cells was specific; it was inhibited by in vitro treatment with ATS, anti-light chain serum, and anti-theta ascitic fluid, but not by removal of mononuclear phagocytes from the immune population. These results are interpreted to mean that recovery mechanisms conferred by immune spleen cells were triggered by specifically sensitized, thymus-derived lymphocytes, and that antibody and interferon responses were of less importance. A radiosensitive recipient component was necessary for the full expression of the antiviral activity of both immune cells and immune serum. It seemed likely that this component was the blood monocyte.

Serum factors in tumor‐free patients cancelling the blocking of cell‐mediated tumor immunity

Abstract: It has been previously shown that lymphocytes from cancer patients can kill cultivated neoplastic cells of the type carried by the lymphocyte donors and that sera from patients with growing tumors of the respective types can specifically block the tumor-cell destruction. The present study demonstrates that sera from all of seven tumor patients tested (one with melanoma, one with colonic carcinoma and four with breast carcinoma), who had become clinically tumor-free, could “unblock” ( = abrogate) the blocking effect of sera from patients bearing tumors of the respective types, thus making it possible for immune lymphocytes to kill cultivated neoplastic cells in the combined presence of the “unblocking” and blocking sera.

Acute immune complex disease in rabbits the role of complement and of a leukocyte-dependent release of vasoactive amines from platelets

Abstract: By depletion of C3 from rabbits undergoing acute experimental immune complex disease with an anticomplementary factor in cobra venom, it has been possible to demonstrate that deposition of the complexes in arteries and glomeruli does not require the complement components reacting after C2. Immunological reactions, in which platelets release their vasoactive amines, have been examined in rabbits undergoing immune complex disease. A correlation was obtained between the presence of a complement-independent reaction which required blood leukocytes, antigen and platelets, the deposition of immune complexes, and the induction of glomerulonephritis. C3 depletion did, however, have a marked alleviating effect on the severity of the arterial lesions. Neutrophil accumulation and the subsequent necrotizing arteritis were prevented. In contrast, the character and severity of the glomerulonephritis was not altered by depletion of later-acting complement components.

Cells mediating specific in vitro cytotoxicity. I. Detection of receptor-bearing lymphocytes.

Abstract: Spleen cells from mice immunized with allogeneic tumor cells are incubated on different fibroblast monolayers. The nonadsorbed cells are tested for cytotoxicity against 51Cr-labeled target cells. The cytotoxicity of nonadsorbed cells is much lower after incubation on fibroblasts syngeneic to the immunizing tumor cells than after incubation on fibroblasts syngeneic to the immune cells. This specific decrease of cytotoxic activity depends on the duration and temperature of incubation on monolayers. After incubation the monolayers are trypsinized and pure populations of adsorbed lymphocytes isolated by density gradient fractionation. The cytotoxicity of such trypsin-eluted, gradient-purified lymphocytes is much higher when these lymphocytes are isolated from fibroblasts syngeneic to the immunizing tumor cells than when they are isolated from fibroblasts syngeneic to the immune cells. These experiments demonstrate specific adsorption of immune cells onto fibroblasts carrying the immunizing antigens, and thus prove the existence of specific receptors at the surface of these immune cells. Spleen cells from mice immunized with two types of allogeneic tumor cells bearing different H-2 antigen alleles are incubated on different fibroblast monolayers. The results of such experiments show a differential specific adsorption pattern, suggesting independent adsorption of two populations of immune cells bearing receptors directed against either one or the other immunizing H-2 antigen. The existence of at least a majority of cells, each of which is homogeneous as to the specificity of its receptors, makes it likely that specific receptors are synthetized by the cells that bear them. The role of specific receptor-bearing cells in the killing process is discussed.

Cell-to-cell interaction in the immune response. Vii. Requirement for differentiation of thymus-derived cells.

Abstract: Experiments were designed to test the possibility that thymus-derived (T) cells cooperate with nonthymus derived (B) cells in antibody responses by acting as passive carriers of antigen. Thoracic duct lymphocytes (TDL) from fowl γG-tolerant mice were incubated in vitro with fowl anti-mouse lymphocyte globulin (FALG), which was shown not to be immunosuppressive in mice. On transfer into adult thymectomized, irradiated, and marrow protected (TxBM) hosts together with a control antigen, horse RBC, a response to horse RBC but not to fowl γG was obtained. By contrast, TxBM recipients of nontolerant, FALG-coated TDL responded to both antigens and the antibody-forming cells were shown to be derived from the host, not from the injected TDL. These findings suggested that, under the conditions of the experiment, triggering of unprimed B cells in the spleens of TxBM hosts was not achieved with antigen-coated tolerant lymphocytes. Another model utilized the ability of B cells to bind antibody-antigen complexes. Spleen cells from TxBM mice, incubated in vitro with anti-fowl γG-fowl γG·NIP, were injected with or without normal TDL (a source of T cells) into irradiated hosts. Only mice given both cell types could produce an anti-NIP antibody response. In a further experiment, spleen cells from HGG·NIP-primed mice were injected together with NIP-coated B cells (prepared as above) into irradiated hosts. A substantial anti-NIP antibody response occurred. If, however, the T cells in the spleens of HGG·NIP-primed mice were eliminated by treatment with anti-θ serum and complement, the NIP response was abolished. It was concluded that antigen-coated B cells could not substitute for T cells either in the primary or secondary response. Treatment of T cells from unprimed or primed mice with mitomycin C impaired their capacity to collaborate with B cells on transfer into irradiated hosts. Taken together these findings suggest that before collaboration can take place T cells must be activated by antigen to differentiate and in so doing may produce some factor essential for triggering of B cells.

Immune response restoration with macrophage culture supernatants.

Abstract: Depression of the in vitro immune response of mouse spleen cell suspensions to sheep erythrocytes by removal of macrophages can be reversed by the addition of supernatants from peritoneal macrophage cultures. Supernatant activity can be absorbed by the red cell antigen, and supernatant-treated red cells are stimulatory in the absence of macrophages or supernatant.

Adjuvant-induced arthritis in rats. ii. drug effects on physiologic, biochemical and immunologic parameters

Abstract: Various parameters in the adjuvant arthritic rat model were investigated for their pharmacologic sensitivity and specificity. Secondary (immune) inflammation and serum lysozyme activity were the most sensitive parameters in detecting anti-inflammatory and immunosuppressive activity. In contrast to anti-inflammatory agents, immunosuppressive agents did not alter the primary (nonimmune) inflammation and did not decrease the severity of secondary inflammation when administered therapeutically. Immunosuppression in the adjuvant arthritic rat model was also detected by depression of hemagglutinin titers. Several agents which are not clinically established anti-inflammatory drugs but which have been reported to elicit anti-inflammatory activity in other experimental models were not effective in decreasing the primary and/or secondary inflammation of adjuvant arthritis. However, certain "nonspecific" agents from various pharmacologic classes were effective in suppressing secondary inflammation. In contrast to anti-inflammatory and immunosuppressive agents, however, these nonspecific agents did not suppress the increase in serum lysozyme activity and/or aggravated adjuvant-induced body weight loss. The results suggest that adjuvant arthritis is a sensitive model, with improved specificity, to detect both anti-inflammatory and immunosuppressive agents. The utilization of immune and nonimmune inflammation, antibody titers, serum lysozyme, body weight changes and various dosing regimens in the adjuvant arthritic rat model aids in elucidating the mechanisms and therapeutic potential of antiarthritic agents.

Genetic Control of Immune Responsiveness

Abstract: Publisher Summary This chapter focuses on the results of experiments conducted to study genetic control of immune responsiveness. Evidence for the presence of histocompatibility linked immune response (Ir) genes was presented or reviewed for a large number of antigens in the workshop. Two immune response genes associated with mouse immunoglobulin allotypes were also described. A brief discussion of the effect of polyanions in restoring the immune response not controlled by histocompatibility linked genes in genetically or surgically athymic mice was also given. It was pointed out that if immune response genes are linked with, but not identical to HL-An antigen, then studies of HL-A disease associations may fail to show such associations because of recombination in a random breeding population. This effect will be lessened if the linkage is very close, or if association of particular Ir and HL-A genes is selected for, or functionally related.

The peritoneal exudate lymphocyte i. differences in antigen responsiveness between peritoneal exudate and lymph node lymphocytes from immunized guinea pigs

Abstract: Peritoneal exudate lymphocytes from guinea pigs immunized with horse radish peroxidase, dinitrophenyl guinea pig albumin, or ferritin in complete Freund's adjuvant have been shown to be significantly more reactive than other lymphocytes in two in vitro assays of cellular immune function: production of macrophage migration inhibitory factor and antigen-induced lymphocyte proliferation. The enhanced reactivity of peritoneal exudate lymphocytes cannot be accounted for by artifacts introduced by column purification or by the presence of nonlymphoid accessory cells. These observations suggest that the peritoneal exudate lymphocyte pool is a highly enriched source of cellular immune effector cells with specificity directed towards those antigenic determinants to which an animal has been recently exposed.

Genetically Determined Immune Deficiency As the Predisposing Cause of “Auto-Immunity” and Lymphoid Neoplasia

Abstract: Burnet has postulated that autoimmunity arises from emergence of “forbidden clones” which make auto-antibody. Our postulate, in contradistinction, is that auto-antibody-producing cells are always present, producing enough autoantibody to remove damaged or aged tissues. In normals, the number of such cells is kept in check by normal T-cells. When T-cell function is defective, the “governing system” controlling auto-antibody producing clones fails, and autoimmune disease, mediated in most diseases by cellular immunity, emerges. The governing mechanism in normals may be one analogous to that which limits the amount of antibody produced to a given antigen, and keeps the antibody (and Ig levels) from continuously rising in normal subjects. Experimental data for this concept are provided by several lines of evidence: 1) Normals have low levels of rheumatoid factor and other “auto-antibodies” in their serum.