Biomedical subjects
Publications and source records attributed to E L Morgan.
Explore the source record for details and available documents.
Fc fragments derived from human immunoglobulin were found to be capable of inducing both a proliferative and polyclonal antibody response in human peripheral blood lymphocyte cultures. The cell population proliferating in response to Fc fragments belongs to the B cell lineage. Expression of polyclonal antibody formation requires the presence of both adherent monocytes and T cells. The role of the monocyte is to enzymatically cleave the Fc fragment into 19,000 mol wt Fc subfragments that are then able to induce polyclonal antibody secretion. Stimulation of polyclonal antibody production by Fc subfragments occurs in the absence of adherent monocytes but still requires the presence of T cells.
Fc fragments derived from human Ig were found to be capable of enhancing T cell-mediated, antigen-induced proliferative and mixed lymphocyte culture responses. Maximum enhancement occurred when suboptimal amounts of antigen or suboptimal numbers of stimulator cells were employed. Augmentation of the allogeneic mixed lymphocyte culture reaction requires an I-A and/or I-B subregion difference between effector and stimulator cell populations. Although a significant proliferative response was observed with K- or D- region differences, Fc fragments were unable to enhance the response. The T cell population acted upon by Fc fragments in the potentiation of these responses bears the Lyt-1(+)23(-) phenotype.
Fc fragments derived from papain digestion of human IgG have the capacity to augment specific T cell-mediated cytolytic responses. The addition of Fc fragments to cultures containing nylon wool-purified effector and irradiated stimulator cells results in a significant enhancement of the cytotoxic response. Fc fragment-mediated enhancement is restricted to those responses in which the allogeneic differences between effector and stimulator populations encompass the H-2 I region. Significant enhancement of the CML response occurs when differences at H-2 K + I + D (B10 alpha B10.BR) and H-2 I (A.TH alpha A.TL) regions are employed. In contrast strain combinations in which only the H-2 D region (B10.A alpha B10.A(2R)) difference occurs no enhancement is seen. The cellular site of Fc adjuvant action in the CML response is the Lyt-1+2- helper T cell. This was concluded from the finding that Lyt-1+2- helper cells had to be present to obtain Fc-augmented CML responses. The substitution of Interleukin 2 for Lyt-1+2- helper T cells maintained the cytotoxic response, but these responses were not susceptible to the enhancing properties of Fc fragments. Moreover, to achieve enhanced cytotoxic response Fc had to interact only with the cell population.
Fc fragments of human IgG stimulate both proliferation and polyclonal antibody formation by B lymphocytes. T lymphocytes, although not proliferating in response to Fc fragments, are triggered to produce a T cell-replacing factor, which substitutes for T cells in the Fc fragment-induced polyclonal response. The factor is produced within 24 hr after Fc stimulation. Neither Fab fragments nor whole IgG have the capacity to stimulate the release of this activity. This material is a product of Lyt 1+23-, Ia-T lymphocytes and requires Ia+ adherent accessory cells for production. The role of the accessory cell is to process the Fc fragments to biologically active 14,000-daltons subfragments, which directly trigger T cells to factor production. This material has been called (Fc)TRF to distinguish it from other T cell factors.
Explore the source record for details and available documents.
The Fc fragment-induced enhancement of the anti-SRBC response was found to be dependent upon the presence of functional macrophages. Fc fragments derived from human immunoglobulin were unable to enhance either the in vivo or in vitro anti-SRBC response in the C3H/HeJ mouse, whereas similar responses in histocompatible C3Heb/FeJ mice were enhanced. Macrophages were found to be required for the Fc fragment-induced adjuvant effect as evidenced by the inability of C3H/HeJ macrophages to substitute for C3Heb/FeJ macrophages in Sephadex G-10-filtered C3Heb/FeJ spleen cell cultures. Moreover, the C3H/HeJ anti-SRBC response could be enhanced when Fc subfragments were employed instead of Fc fragments. The C3H/HeJ-derived T cells were normal, since they could be added to B cells and macrophages derived from the C3Heb/FeJ mouse with an enhanced response observed in the presence of Fc fragments. The fact that C3H/HeJ macrophages function normally as accessory cells in generation of the anti-SRBC response but fail to function in the Fc-induced adjuvant effect allows the dissection of 3 macrophage functions in the modulation of the antibody response.
Explore the source record for details and available documents.
Fc fragments derived from human and murine Ig were found to be potent adjuvants when administered with antigen. Both the in vivo and in vitro anti- sheep erythrocytes (SRBC) responses were significantly enhanced by Fc fragments. The adjuvant effect was shown to be extremely dependent upon the dose of antigen used, with the greatest enhancement occurring when suboptimal doses of antigen are employed. The anti-genicity of the Fc molecule was not related to its adjuvanticity because homologous Fc was as potent an adjuvant as heterologous Fc. Moreover, human Fc fragments enhanced anti-SRBC responses in mice which were tolerant to human gamma globulin.
Explore the source record for details and available documents.
Murine splenic lymphocytes proliferate in response to supernatant material derived from Fc fragment-pulsed splenic adherent cells. The stimulatory supernatant results from the interaction of Fc fragments with adherent cells or adherent cell supernate. Isolation of the stimulatory material in the supernate by Sephadex chromatography revealed that the mitogenic component was a cleavage product of Fc with a mol wt of approximately 14,000. The spleen cell type responsible for the generation of mitogenic Fc subfragments appears to be a macrophage. Unstimulated macrophages release an active supernate without being exposed to Fc fragments. The supernate of unstimulated macrophages apparently contain an enzyme which is capable of cleaving Fc fragments into the 14,000-mol wt mitogenic molecules. The spleen cell population induced to proliferate in response to the adherent cell supernate is present in T-cell depleted and Sephadex G-10 filtered cell preparations. Depletion of cells bearing immunoglobulin on their surfaces results in a reduced proliferative response to the mitogenic supernatant material indicating that it is probably a B cell.
T lymphocytes are stimulated to release T-cell-replacing factors in response to Fc fragments of human IgG, Lyt 1+23- T cells are directly triggered to factor production by Fc subfragments, derived from intact Fc fragments by macrophage-dependent enzymatic cleavage. These factor(s) replace T cell function in two Fc-mediated immune responses; induction of polyclonal antibody synthesis, and potentiation of anti-SRBC responses.
Murine splenic B lymphocytes are induced to proliferate and undergo polyclonal activation in the presence of Fc fragments, AHGG, antigen-antibody complexes, and CH3 fragments derived from plasmin digestion of human Ig. The unifying feature of the polyclonal antibody response induced by these agents is that in all cases a portion of the constant region of the Ig molecule (ie, Fc region) is present. Fragments of Ig lacking the Fc piece, such as Fab and F(ab)2 were found not to be stimulatory. In addition, a model is proposed to account for the regulatory effects of antigen-antibody complexes on an ongoing humoral immune response.
Explore the source record for details and available documents.
Murine splenic B lymphocytes are stimulated to proliferate and undergo polyclonal activation in the presence of heat-aggregated human gamma-globulin (AHGG). Splenic macrophages are required to generate the proliferative and polyclonal antibody responses. The polyclonal response as opposed to the proliferative response is dependent upon the presence of T lymphocytes. The stimulatory molecule responsible for the AHGG-induced proliferative and polyclonal activation is derived from incubation of AHGG with splenic macrophages. The biologically active moiety is derived from the Fc portion of the HGG molecule and is approximately 14,000 m.w. The method of aggregation is critical for the generation of stimulatory HGG preparations. Heat aggregation is the only method produced a biologically active preparation
Fc fragments derived from human IgG1 induce murine splenic B lymphocytes to undergo proliferation and differentiation to antibody-secreting cells. The polyclonal antibody response was found to require both the presence of macrophages and T cells. Spleen cell cultures from nude mice or T cell-depleted normal mice proliferate to the level of untreated control mice but do not produce polyclonal antibody unless T cells are added. Regulation of the Fc fragment induced B cell differentiation to antibody synthesis apparently occurs through two distinct signals. One signal is provided by Fc fragments for proliferation and the other by T cells for differentiation. This suggestion is supported by the observation that spleen cell preparations, devoid of T cells, are capable of proliferation to the level of normal spleen cell cultures in response to Fc fragments, but are incapable of making a polyclonal antibody response. The cell population that responds to the differentiation signal also responds to the proliferative signal. "Hot pulse" experiments demonstrated that proliferation precedes polyclonal activation.
Fc fragments of human gamma-globulin stimulate T cell-dependent polyclonal antibody responses in murine splenic B cells. The T cell signal can be delivered by a soluble T cell-replacing factor, derived by concanavalin A stimulation of spleen cells. TRF interacts directly with responding B cells and appears to provide the second, differentiative, trigger that initiates the polyclonal response. TRF is maximally active even if added at 24 hr after Fc and does not alter the response kinetics. Although macrophages are requird for the polyclonal activation of B cells in intact spleen cell cultures, they are not necessary for the delivery of the TRF signal to B cells.
Spleen cell preparations from the C3H/HeJ mouse were found to be refractory to Fc fragment-induced polyclonal activation. This defect was not a characteristic of all C3H strains, because spleen cells from the histocompatible C3Heb/FeJ strain produced polyclonal antibody in the presence of Fc fragments. The cellular defect was found to be associated with the macrophage population. Macrophages from C3H/HeJ mice were incapable of generating mitogenic Fc subfragments from intact Fc, whereas C3Heb/FeJ performed this function normally. That T cells and B cells from the C3H/HeJ mouse were normal was shown by the fact that C3H/HeJ spleen cells responded to Fc subfragments. Moreover, T cells from C3H/HeJ spleen cell populations could be substituted for C3Heb/FeJ-derived T cells.