[Rhythm control - cardioversion]. / Contrôle du rythme sinusal - Cardioversion.

In case of persistent and symptomatic atrial fibrillation, a pharmacological cardioversion under effective anticoagulation treatment may be performed according to current guidelines. In the absence of return to sinus rhythm, a Direct-Current cardioversion can be performed. After returning to sinus rhythm will arise the question of anticoagulation and antiarrhythmic drugs treatments that will be most often long-term pursued.

A role for L3T4+ T cells and their lymphokines in the generation of suppressor effector (TS3) cells.

The cellular requirements for the in vitro induction of antigen-specific suppressor T cells were examined. Previous reports indicated that Ia-bearing macrophages and anti-idiotypic B cells are required as accessory cells to facilitate the generation of suppressor effector (TS3) cells which regulate the response to the 4-hydroxy-3-nitrophenyl acetyl (NP) hapten. The present study describes two distinct T cell populations which interact to generate antigen-specific TS3. Fractionation of the T cell populations with monoclonal antibody to the L3T4 determinant led to the identification of an NP-specific L3T4- TS3 progenitor population and an L3T4+ helper/inducer subset. In the presence of NP-coupled antigen, the L3T4+ subset could induce progenitor TS3 to differentiate into mature TS3 cells. The activity of the L3T4+ inducer population could be replaced with specifically activated cloned helper cells which were not NP-reactive since an I-Ab-restricted, insulin-reactive, L3T4+ clone was capable of supporting the generation of NP-specific TS3. Inducer activity appeared to be confined to the Th1 but not the Th2 subset. In addition, 18-hr supernatants from antigen-activated clones were capable of substituting for L3T4+ cells or T cell clones in TS3 induction cultures. The TS maturation/differentiation factor(s) active in these supernatants does not appear to be IL-1, IL-2, IL-3, or interferon-gamma alone since purified sources of these lymphokines failed to induce TS3 activity.

The role of adherent accessory cells in the generation of effector suppressor T cells.

The role of accessory cell populations in the generation of effector suppressor (Ts3) cells was studied. By using an in vitro culture system, it was previously determined that the induction of NP-specific effector suppressor activity requires T cells, antigen, and an anti-idiotypic B cell population. We now demonstrate that the generation of Ts3 cells in this system also requires accessory cells. The accessory population appears to play a role in the processing and presentation of antigen. These antigen-presenting accessory cells are required early in the induction phase of Ts3 generation. These accessory cells can present NP coupled to immunogenic or non-immunogenic polypeptide carriers, including polymers of L-amino acids. However, NP coupled to polymers of poorly metabolized D-amino acids fail to induce suppressor T cell generation. Furthermore, the data demonstrate that an H-2 homology must exist between the Ts3 precursors and the antigen-presenting cell population if suppressor activity is to be generated. We also characterize the differential genetic restrictions that govern the induction of Ts3 cells that control suppression of either T cell or B cell responses. The data suggest that although I-J region encoded gene products control the induction and effector phases of suppressor cell activity as measured on T cell responses, the suppression of B cell responses appear to be controlled by I-A gene products. Possible cellular mechanisms that might explain these findings are discussed.

Regulation of hapten-specific T and B cell responses by suppressor cells.

We have described a model system of immunoregulation in which gene products associated with both the H-2 and Igh complexes guide a series of cellular interactions. The Igh restriction represents the requirement for T cell recognition of Igh-linked NPb-related idiotypic determinants. The data provide additional evidence that the T and B cell Igh products are distinct. Immunoglobulin products are involved in the selection of T cell receptors; Igh genes are not expressed in T suppressor cell. The H-2 restrictions generally involve the I-J subregion. These restrictions are imposed by the presentation of antigen or suppressor factor on a specialized population of I-J bearing, antigen-presenting cells, thereby functioning in a manner analogous to that proposed for the induction of helper T cells. The NP suppressor cell pathway consists of multiple cellular elements, including at least 3 distinct T cell populations and 2 or more distinct antigen-presenting populations. Generally, specific soluble suppressor factors produced by each Ts cell subset are involved in the cellular communication process. The terminal phases of the suppressor cell cascade involve an antigen dependent non-specific bystander mechanism. Tables IX and X summarize our present view of the NP suppressor cell cascade. It is still not possible to include all the other experimental models involving suppressor cell interactions into the above scheme. However, the disparities between the various systems have in some cases narrowed and in other instances suggested that multiple mechanisms of immune regulation may occur concurrently.

Anti-idiotypic B cells are required for the induction of suppressor T cells.

A nylon wool-adherent, B cell-enriched population is required during the in vitro induction of third order effector suppressor T cells (Ts3). This B cell population expresses IgM and IgD and is devoid of conventional T cell markers such as Thy-1, L3T4, and Lyt-1. Treatment of the B cell population with anti-NP antibodies expressing the NPb idiotype and complement specifically eliminated the ability to generate Ts cell activity, suggesting that the critical B cells expressed anti-idiotypic receptors. To independently verify the role of anti-idiotypic B cells in the generation of Ts cells, B cells were panned on antibody-coated plates. The results demonstrated that only NPb idiotype-binding B cells could induce effector suppressor cells from naive T cell populations. The combined data demonstrate the role of Ig network interactions in the generation of Ts cells.

Mechanism controlling the genetic restrictions of an NP-specific suppressor factor that inhibits B cell responses.

The mechanism of B cell suppression by a T cell hybridoma-derived monoclonal effector suppressor factor (TsF3) was studied in the 4-hydroxy-3-nitrophenyl acetyl (NP) system. The NP-specific effector suppressor cells that produce TsF3 are Lyt-1-, 2+, I-J+, NP-binding T cells and are induced by immunization with NP conjugates. Monoclonal TsF3 inhibits both T cell activity as measured by suppression of contact sensitivity responses and B cell function as measured by suppression of antibody production to both T-independent and T-dependent antigens. The present studies were designed to specifically investigate the mechanisms and genetic restrictions that govern the interactions between TsF3 and its target cells in the plaque-forming cell (PFC) response. The results show that the target of TsF3 is a splenic adherent cell. Suppression will occur only if the restriction specificity of the TsF3 matches the H-2 genotype of the adherent population. Once this TsF3-adherent cell interaction has occurred, suppression of NP-specific B cells can occur across an H-2 barrier. The data also demonstrate that Igh-linked gene products do not appear to play a part in the TsF3-mediated suppression of in vitro PFC responses, which contrasts with the requirements for regulation of T cell-mediated contact sensitivity responses.

Immunological studies of ageing. X. Impaired T lymphocytes and normal monocyte response from elderly humans to the mitogenic antibodies OKT3 and Leu 4.

Lymphocytes from old and young humans were cultured with PHA or the monoclonal antibodies OKT3 or Leu 4. The incorporation of [3H]TdR was significantly lower in cultures from old as compared to young donors, and the response of lymphocytes stimulated with OKT3 was the best discriminator of donor age. The mitogenic response of lymphocytes to these monoclonal antibodies requires monocytes. The response of T cells containing less than 5% adherent cells was diminished and the difference between old and young donors was not seen. The age-associated response was recovered when autologous or allogeneic monocytes were added to T cells. The age-associated response of T cells was the same, whether cultured with monocytes from young or old donors. Thus, monocytes from elderly subjects are not impaired with respect to their capacity to facilitate the proliferative response of T cells stimulated with monoclonal antibodies. Although lymphocytes from elderly donors were more sensitive to the inhibitory effect of prostaglandin E2, this did not account for the age-associated defect as indomethacin did not eliminate this defect. We conclude that the proliferative response of lymphocytes to OKT3 and Leu 4 is a more sensitive discriminator of lymphocyte donor age than is response to plant lectins, and that the age-associated defect in this response appears to reside within the T-cell population and not the monocyte population.

Immunological studies of aging. XI. Age-related changes in idiotype repertoire of suppressor T cells stimulated during tolerance induction.

Tolerance was induced in young and old mice by the i.v. injection of TNP-modified syngeneic spleen cells. The tolerant state was associated with the development of hapten-specific suppressor T cells. The specificity of suppressor T cells was studied by transferring T cells from tolerant donors to normal, nonirradiated, syngeneic recipients, which were then immunized with TNP-Ficoll or TNP-bovine gamma-globulin. Suppressor T cells induced in young mice depressed the plaque-forming cell response of young but not old mice to both antigens. Similarly, suppressor T cells induced in old mice depressed the response in old but not young mice. These findings suggest that aging is associated with changes in idiotype repertoire which influence the specificity of the suppressor T cells present in tolerant mice.

An in vitro system for the generation of suppressor cells and the requirement for B cells in their induction.

An in vitro method for the generation of effector suppressor cells (Ts3) was developed. By utilizing this protocol, it was possible to investigate both the cellular and genetic requirements for suppressor cell induction. It was determined that populations containing Ts3 cells can be induced after a 4-day culture of spleen cells and antigen. These Ts3 cells are similar to Ts3 cells generated by in vivo immunization. Both populations are I-J+, bind NP hapten, bind NP hapten, bear receptors which share NPb idiotypic determinants with anti-NP antibodies, function during the effector phase of the immune response, and require activation with Ts2 cells. Generation of Ts3-containing populations required both nylon wool-nonadherent T cells and a nylon-adherent, B cell-enriched population from an Igh-identical donor. T cells cultured with antigen alone or with syngeneic macrophages and antigen did not develop suppressive activity. Lytic treatment of the nylon-adherent population with a B cell-specific monoclonal antibody (J11d) removed the ability to generate suppressor cells. These results imply that the induction of suppressor T cells requires B lymphocytes, and that this induction process is dependent on Igh-linked gene products.

Studies on the syngeneic mixed lymphocyte reaction. III. Development of a monoclonal antibody with specificity for autoreactive T cells.

Monoclonal antibodies with specificity for autoreactive murine T cells have been developed. These antibodies inhibit proliferative response of splenic T cells activated by syngeneic spleen cells. These antibodies have no effect on the proliferative response of T cells activated by allogeneic spleen cells or PHA. The number of splenic T cells that react with these monoclonal antibodies is comparable in several normal mouse strains.

The developmental biology of the syngeneic mixed lymphocyte reaction.

The syngeneic mixed lymphocyte reaction (SMLR) is the proliferative response of T lymphocytes cultured with non-T lymphocytes. Normal mouse serum supports proliferative activity in the SMLR comparable to levels observed when fetal calf serum is used. Thus, the SMLR does not appear to be a response to xenogeneic antigens. The ontogeny and senescence of the SMLR was also studied. The SMLR is impaired in mice less than 4 weeks of age but attains adult levels of activity at 4 weeks of age. The SMLR is also impaired in 24-month-old mice. These impairments were observed regardless of the source of serum used in the cultures. Finally, monoclonal antibodies have been developed which identify a subpopulation of spleen cells which respond in the SMLR. In indirect immunofluorescence these antibodies stain 50-80% of cells activated in the SMLR, but only 5-8% of spleen cells or cells activated in the allogeneic MLR. These antibodies block the proliferative response in the SMLR but do not interfere with the response to alloantigens or PHA.

The autologous mixed lymphocyte reaction in systemic lupus erythematosus.

The autologous mixed lymphocyte reaction (AMLR) represents the proliferation of T cells in response to signals from autologous non-T cells. Fractionation of the non-T population into B enriched and macrophage enriched cells demonstrated that both could serve as effective stimulator cells in the AMLR. Cytolytic treatment of both populations with a macrophage specific, monoclonal antibody abrogated stimulation of the macrophage but not the B cell population. Utilizing a series of negative selection procedures - cytolysis with T cell specific monoclonal antibody, metabolic suicide with 5-bromo-2-deoxyuridine (brdU) and light - it could be demonstrated that T cells responding to autologous macrophage were distinct from those responsive to autologous B cells. Studies of the AMLR reactivity to B cells and macrophage in a small number of patients with active systemic lupus erythematosus (SLE) demonstrated that although reactivity to both populations was diminished, the response to autologous B cells was reduced more than the response to autologous macrophage. These studies suggest that the AMLR represents the sum reactivities of two responder T cells. Moreover, they suggest that a relatively selective deficiency in only one of these cells may occur in SLE.

Antigen-reactive T cells can be activated buy autologous macrophages in the absence of added antigen.

T cells responsive to macrophages (M phi) in the autologous mixed lymphocyte reaction (AMLR) contain those cells that can be induced to proliferate by soluble antigens. Negative solution (5-bromo-2-deoxyuridine and light) of T cells activated by autologous M phi also removed those cells required for reactivity to Candida albicans and purified protein derivative. Positive selection of T cells responsive to autologous M phi yields a population that is simultaneously enriched in antigen reactivity. Some patients demonstrating cutaneous anergy and diminished in vitro blast transformation in response to soluble antigen also lack T cells responsive to the AMLR to M phi. When considered in conjunction with previously reported data, these findings indicate the AMLR occurring between T cells and M phi in the absence of soluble antigen represents self recognition occurring between antigen-reactive T cells and antigen-presenting M phi.

Specificity and function of a human autologous reactive T cell.

Normal human peripheral blood contains a population of T cells (autologous reactive cells [ARC]) capable of proliferating in response to signals from autologous B cells and monocytes. Selective suicide of proliferating ARC with 5-bromo-2-deoxyuridine and light demonstrated that this ARC was responsive to signals coded for by genes more closely linked to the HLA-DR, than to the HLA-A, or HLA-B, loci. Density-gradient fractionation of T cells indicated that populations enriched in ARC reactivity were also enriched for helper influences required for Ig synthesis by autologous B cells. In contrast, populations negatively selected for proliferating ARC were deficient in helper activity. These studies indicate that the ARC is responsive, at least in part, to products of genes closely linked to the HLA-DR locus and can function as a helper cell.