Cellular sites of immunologic unresponsiveness.
01 Mar 1970-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 65, Iss: 3, pp 551-556
TL;DR: The reconstitution of the immune response of lethally irradiated mice to human gamma-globulin is dependent on the synergistic action of bone marrow with thymus cells, but neither bone marrow nor thymUS cells from unresponsive donors are capable of demonstrating synergism in combination with their normal counterpart.
Abstract: The reconstitution of the immune response of lethally irradiated mice to human γ-globulin is dependent on the synergistic action of bone marrow with thymus cells. Immunologic unresponsiveness appears to involve a functional defect at each of these cellular levels, inasmuch as neither bone marrow nor thymus cells from unresponsive donors are capable of demonstrating synergism in combination with their normal counterpart.
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TL;DR: The foregoing requirements provide an explanation for self-nonself discrimination, which involves a specific deletion in the activity of both the humoral- and the carrier-antigen-sensitive cells.
Abstract: 1) Induction of humoral antibody formation involves the obligatory recognition of two determinants on an antigen, one by the receptor antibody of the antigen-sensitive cell and the other by carrier antibody (associative interaction). 2) Paralysis of antibody formation involves the obligatory recognition of only one determinant by the receptor antibody of the antigen-sensitive cell; that is, a nonimmunogenic molecule (a hapten) can paralyze antigen-sensitive cells. 3) There is competition between paralysis and induction at the level of the antigen-sensitive cell. 4) The mechanisms of low- and high-zone paralysis, and maintenance of the unresponsive state, are identical. 5) High-zone paralysis occurs when both the carrier antibody and the receptor antibody are saturated, so that associated interactions cannot take place. 6) The mechanisms of paralysis and induction for the carrier-antigen-sensitive cell are identical to those for the humoral-antigen-sensitive cell. 7) The formation of carrier-antigen-sensitive cells is thymus-dependent, whereas humoral-antigen-sensitive cells are derived from bone marrow. Since carrier antibody is required for induction, all antigens are thymus-dependent. 8) The interaction of antigen with the receptor antibody on an antigen-sensitive cell results in a conformational change in an invariant region of the receptor and consequently paralyzes the cell. As the receptor is probably identical to the induced antibody, all antibody molecules are expected to be able to undergo a conformational change on binding a hapten. The obligatory associated recognition by way of carrier antibody (inductive signal) involves a conformational change in the carrier antibody, leading to a second signal to the antigen-sensitive cell. 9) The foregoing requirements provide an explanation for self-nonself discrimination. Tolerance to self-antigens involves a specific deletion in the activity of both the humoral- and the carrier-antigen-sensitive cells.
1,701 citations
TL;DR: Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX.
Abstract: OBJECTIVE: To evaluate the efficacy, pharmacokinetics, immunogenicity, and safety of multiple infusions of a chimeric monoclonal anti-tumor necrosis factor alpha antibody (cA2) (infliximab; Remicade, Centocor, Malvern, PA) given alone or in combination with low-dose methotrexate (MTX) in rheumatoid arthritis (RA) patients. METHODS: In a 26-week, double-blind, placebo-controlled, multicenter trial, 101 patients with active RA exhibiting an incomplete response or flare of disease activity while receiving low-dose MTX were randomized to 1 of 7 groups of 14-15 patients each. The patients received either intravenous cA2 at 1, 3, or 10 mg/kg, with or without MTX 7.5 mg/week, or intravenous placebo plus MTX 7.5 mg/week at weeks 0, 2, 6, 10, and 14 and were followed up through week 26. RESULTS: Approximately 60% of patients receiving cA2 at 3 or 10 mg/kg with or without MTX achieved the 20% Paulus criteria for response to treatment, for a median duration of 10.4 to >18.1 weeks (P 60% of patients to a median of 16.5 weeks (P < 0.001 versus placebo; P=0.006 versus no MTX) and the 50% response to 12.2 weeks (P < 0.001 versus placebo; P=0.002 versus no MTX). Patients receiving placebo infusions plus suboptimal low-dose MTX continued to have active disease, with a Paulus response lasting a median of 0 weeks. A 70-90% reduction in the swollen joint count, tender joint count, and C-reactive protein level was maintained for the entire 26 weeks in patients receiving 10 mg/kg of cA2 with MTX. In general, treatment was well tolerated and stable blood levels of cA2 were achieved in all groups, except for the group receiving 1 mg/kg of cA2 alone, at which dosage antibodies to cA2 were observed in approximately 50% of the patients. CONCLUSION: Multiple infusions of cA2 were effective and well tolerated, with the best results occurring at 3 and 10 mg/kg either alone or in combination with MTX in approximately 60% of patients with active RA despite therapy with low-dose MTX. When cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed. The results of the trial provide a strategy for further evaluation of the efficacy and safety of longer-term treatment with cA2.
1,673 citations
TL;DR: Clinical investigations in which the activity of TNF alpha in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNF alpha monoclonal antibody (mAB), has provided evidence that TNF regulates IL-6, IL-8, MCP-1, and VEGF production, recruitment of immune and inflammatory cells into joints, angiogenesis, and reduction of blood levels of matrix metalloproteinases-1 and -3.
Abstract: Rheumatoid arthritis (RA), a systemic disease, is characterized by a chronic inflammatory reaction in the synovium of joints and is associated with degeneration of cartilage and erosion of juxta-articular bone. Many pro-inflammatory cytokines including TNFα, chemokines, and growth factors are expressed in diseased joints. The rationale that TNFα played a central role in regulating these molecules, and their pathophysiological potential, was initially provided by the demonstration that anti-TNFα antibodies added to in vitro cultures of a representative population of cells derived from diseased joints inhibited the spontaneous production of IL-1 and other pro-inflammatory cytokines. Systemic administration of anti-TNFα antibody or sTNFR fusion protein to mouse models of RA was shown to be anti-inflammatory and joint protective. Clinical investigations in which the activcity of TNFα in RA patients was blocked with intravenously administered infliximab, a chimeric anti-TNFα monoclonal antibody (mAB), has prov...
1,300 citations
Journal Article•
TL;DR: The immunosuppressive effect of the presence of thymocytes during the antigen Pretreatment was studied by adoptively transferring the spleen cells of the antigen pretreated mice to thymus-deprived chimeras.
Abstract: Previous studies have shown that thymectomized lethally irradiated bone marrow grafted mice, reconstituted with thymocytes and pretreated with a large dose of sheep red blood cells (SRBC), are unable to respond to a subsequent immunizing injection of SRBC even after an inoculation of normal thymocytes. If, however, the mice are not thymocyte reconstituted prior to the pretreatment with SRBC, they can respond almost normally to an immunizing injection of SRBC if inoculated with normal thymocytes after the termination of antigen pretreatment.In the present study the immunosuppressive effect of the presence of thymocytes during the antigen pretreatment was studied by adoptively transferring the spleen cells of the antigen pretreated mice to thymus-deprived chimeras. These spleen cells not only did not co-operate with normal thymocytes in the secondary hosts, but they also prevented the co-operation of normal thymocytes with normal bone marrow derived cells. Untreated spleen cells or treated spleen cells from mice not reconstituted with thymocytes did not affect cell co-operation in the secondary hosts. The abrogation of the co-operation in the secondary host was specific in that the addition of spleen cells did not affect the anti-horse red blood cell response. If the primary host made antibody as a result of the pretreatment, the transfer of their spleen cells did not prevent antibody production in the secondary host.
811 citations
TL;DR: Progress in the characterization of intercellular mediators — proteins that are now known as cytokines — has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-α), has an important role in the pathogenesis of rheumatoid arthritis.
Abstract: The aetiology of systemic, autoimmune, chronic inflammatory diseases--such as rheumatoid arthritis--is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators--proteins that are now known as cytokines--has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-alpha), has an important role in the pathogenesis of rheumatoid arthritis. This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases.
683 citations
Cites background from "Cellular sites of immunologic unres..."
...Analysis of the patients' antibody response to the chimeric antibody revealed that immunogenicity was inversely proportional to dose, which is highly reminiscent of the classical immunological phenomenon of high-zone tolerance — in which high doses of deaggregated antigen injected intravenously induce immunological tolerance — that was first described in the late 1960...
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References
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TL;DR: The 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.
Abstract: The number of discrete hemolytic foci and of hemolysin-forming cells arising in the spleens of heavily irradiated mice given sheep erythrocytes and either syngeneic thymus or bone marrow was not significantly greater than that detected in controls given antigen alone. Thoracic duct cells injected with sheep erythrocytes significantly increased the number of hemolytic foci and 10 million cells gave rise to over 1000 hemolysin-forming cells per spleen. A synergistic effect was observed when syngeneic thoracic duct cells were mixed with syngeneic marrow cells: the number of hemolysin-forming cells produced in this case was far greater than could be accounted for by summating the activities of either cell population given alone. The number of hemolytic foci produced by the mixed population was not however greater than that produced by an equivalent number of thoracic duct cells given without bone marrow. Thymus cells given together with syngeneic bone marrow enabled irradiated mice to produce hemolysin-forming cells but were much less effective than the same number of thoracic duct cells. Likewise syngeneic thymus cells were not as effective as thoracic duct cells in enabling thymectomized irradiated bone marrow-protected hosts to produce hemolysin-forming cells in response to sheep erythrocytes. Irradiated recipients of semiallogeneic thoracic duct cells produced hemolysin-forming cells of donor-type as shown by the use of anti-H2 sera. The identity of the hemolysin-forming cells in the spleens of irradiated mice receiving a mixed inoculum of semiallogeneic thoracic duct cells and syngeneic marrow was not determined because no synergistic effect was obtained in these recipients in contrast to the results in the syngeneic situation. Thymectomized irradiated mice protected with bone marrow for a period of 2 wk and injected with semiallogeneic thoracic duct cells together with sheep erythrocytes did however produce a far greater number of hemolysin-forming cells than irradiated mice receiving the same number of thoracic duct cells without bone marrow. Anti-H2 sera revealed that the antibody-forming cells arising in the spleens of these thymectomized irradiated hosts were derived, not from the injected thoracic duct cells, but from bone marrow. It is concluded that thoracic duct lymph contains a mixture of cell types: some are hemolysin-forming cell precursors and others are antigen-reactive cells which can interact with antigen and initiate the differentiation of hemolysin-forming cell precursors to antibody-forming cells. Bone marrow contains only precursors of hemolysin-forming cells and thymus contains only antigen-reactive cells but in a proportion that is far less than in thoracic duct lymph.
565 citations
TL;DR: It was found that both adherent and nonadherent cells were necessary for the induction of antibody formation to sheep red blood cells in vitro.
Abstract: A suspension of mouse spleen cells can be separated into two populations on the basis of their ability or inability to adhere to plastic dishes. It was found that both adherent and nonadherent cells were necessary for the induction of antibody formation to sheep red blood cells in vitro. Exposure of adherent cells to antigen for brief periods of time was sufficient to initiate a maximal in vitro response.
561 citations
TL;DR: Suspensions containing normal thymus, spleen, or marrow cells were injected into irradiated syngeneic mice which were subsequently given antigen and mice receiving both marrow and thymUS cells produced more centers of hemolytic activity in their spleens than mice receiving cells of either type alone.
Abstract: SummarySuspensions containing normal thymus, spleen, or marrow cells were injected into irradiated syngeneic mice which were subsequently given antigen. Normal spleen cells produced discrete areas ...
538 citations
TL;DR: The results are discussed in terms of a possible mechanism of antibody production in which an RNAse-sensitive substance resulting from the interaction of macrophages and antigen is capable of stimulating antibody synthesis in lymphocytic cells.
Abstract: Neutralizing activity against T2 bacteriophage appeared in cultures of lymph node cells from normal rats in response to their in vitro stimulation with a cell-free filtrate derived from homogenized rat macrophages which had been incubated with T2 bacteriophage. This activity was specifically directed against T2 bacteriophage. It resided in a fraction of the culture fluid which had the salting-out properties of serum globulin. Phage neutralization was inhibited by antibody specific for rat serum gamma globulin. Antibody production against T2 bacteriophage in cultures of lymph node cells from normal animals failed to occur if (a) T2 bacteriophage alone was added, (b) if the incubation period of macrophages and T2 phage was unduly shortened, (c) if the cell-free filtrate was heated at 80–100°C for 15 minutes, (d) if more than an optimal amount of T2 bacteriophage was added to the macrophages. Additional factors which prevented the formation of antibody were the heat inactivation of the lymph node cells or the addition to the culture medium of either streptomycin or ribonuclease. Finally, it was found that macrophages and lymph node cells had to be obtained from animals of one and the same species. All essential findings on the production of antibody to T2 bacteriophage in vitro could be confirmed by substitution of the chick embryo for the tissue culture medium. The results are discussed in terms of a possible mechanism of antibody production in which an RNAse-sensitive substance resulting from the interaction of macrophages and antigen is capable of stimulating antibody synthesis in lymphocytic cells.
380 citations
Journal Article•
TL;DR: The method is simple and sensitive and the results mimic the kinetics of the response that is seen in in vivo assays of serum antibody.
Abstract: Summary A method is presented which allows the in vitro enumeration of cells producing antibody against a variety of protein antigens. The proteins are covalently linked to red blood cells by means of a carbodiimide reagent. The concentrations of protein required for the plaque assay are greater than those required for passive agglutination. The method is simple and sensitive and the results mimic the kinetics of the response that is seen in in vivo assays of serum antibody. Both direct (probably 19 S) and indirect (probably 7 S) plaque-producing cells are detected.
197 citations