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Biomedical subjects

M L Thoman

Publications and source records attributed to M L Thoman.

At least 37 records · Page 2Linked to original sources
PubMed1987

Retention of T cell reactivity to mitogens and alloantigens by Peyer's patch cells of aged mice.

Immune function generally declines with advancing age. However, recent evidence suggests that this decline may differentially affect the lymphoid compartments comprising the immune system. The effect of age on the T cell-mediated competency of cells from two different lymphoid compartments, Peyer's patch (PP) and spleen, was studied. PP cells of aged C57BL/6 mice retained a greater capacity to proliferate in response to concanavalin A, phytohemagglutinin, and alloantigen and to generate alloimmune cytotoxic cells than did splenocytes of aged mice when compared with their young counterparts. These results could not be explained by significant shifts in the response kinetics or in the proportions of T cells in individual tissues. These results support the concept that lymphoid compartments are not equally sensitive to the deleterious effects of the aging process.

Aging↗
PubMed1985

Human C3a-mediated suppression of the immune response. II. Suppression of human in vitro polyclonal antibody responses occurs through the generation of nonspecific OKT8+ suppressor T cells.

C3a-mediated suppression of Ig secretion in human PBL cultures occurs through the activation of suppressor T cells. Incubation of T cell-enriched populations derived from peripheral blood or tonsil results in the activation of nonspecific OKT3+8+ suppressor T cells capable of inhibiting Fc fragment-induced Ig secretion in fresh autologous PBL cultures. Generation of OKT8+ suppressor T cells by C3a requires the interaction of T cells, adherent cells, and C3a. Activation of the suppressor-T-cell pathway is initiated early in culture. Incubation of the T-cell-enriched populations with C3a for 0.5 hr results in functional, transferable suppressor cells. Maximum suppression was achieved when C3a was allowed to interact with the cell population for 1-2 hr.

Antibody Formation↗
PubMed1985

Bioactive complement fragments in immunoregulation.

Several fragments derived from complement components have been identified as potent effector substances in in vitro assays that measure cell proliferation and antibody synthesis. The anaphylatoxin C3a suppresses the immune response but fails to influence T- or B-cell proliferation. The factor C5a augments both antibody production and antigen-induced, but not mitogen-induced, T-cell proliferation. C3a-mediated suppression occurs through the activation of a suppressor T-cell cascade with macrophage collaboration. C5a-mediated enhancement, depending upon the in vitro system studied, acts at the level of the helper T cell and/or macrophage. A fragment generated from treating iC3b with kallikrein (c3d-K) has aided in defining a structural region of the C3b molecule that can influence the level of circulating leukocytes. The factor C3d-K is also capable of suppressing both specific and non-specific T-cell proliferative responses and mitogen-induced B cell growth. The mechanism of C3d-K action is defined as a direct effect on "activated" T cells, even though IL-2 synthesis of treated cells is diminished. The effect of C3d-K is long lasting, non-reversible and requires only a short exposure to the target cell.

Animals↗
PubMed1985

Human C3a-mediated suppression of the immune response. I. Suppression of murine in vitro antibody responses occurs through the generation of nonspecific Lyt-2+ suppressor T cell.

C3a derived from the third component of human complement was found to suppress in vitro murine anti-SRBC responses. C3a-mediated suppression occurs through the generation of nonspecific Lyt-2+ suppressor T cells. The generation of suppressor cells occurs at an early phase in the response because incubation of naive T cells with C3a for as little as 30 min results in suppression of the anti-SRBC response. The generation of suppressor T cells requires the interaction of T cells, C3a, and a Sephadex G-10-adherent cell, presumably a macrophage. Although the mechanism of action of these suppressor cells has not been elucidated, several possibilities have been eliminated. C3a-suppressor T cells do not apparently release inhibitory lymphokines, nor is helper cell activity inhibited by a 2-day co-culture with these suppressor cells. The observation that interleukin 2 (IL 2)-containing lymphokine preparations could overcome C3a-induced suppression led us to investigate the interaction of the suppressors with IL 2 producer cells. However, neither C3a nor C3a-generated suppressor T cells can block the synthesis of IL 2.

Animals↗
PubMed1985

Reconstitution of in vivo cell-mediated lympholysis responses in aged mice with interleukin 2.

Advancing age is accompanied by declining immune potential. Both humoral and cellular immune responses are diminished in aged humans and experimental animals. A major lesion preventing effective T cell-mediated responses is the lack of interleukin 2 (IL 2) synthesis in aged mice. Addition of IL 2 can effectively reconstitute in vitro T cell-dependent humoral and cell-mediated immunity. These results have been extended, demonstrating that IL 2-containing lymphokine preparations when administered with antigen can restore the ability of aged mice to generate cytotoxic T lymphocytes in vivo. Furthermore, IL 2 has been identified as the active component of these lymphokine preparations through the use of purified human IL 2 prepared by recombinant DNA and gene cloning technology. The cloned IL 2 is highly effective in enhancing the immune responses of aged animals both in vitro and in vivo.

Aging↗
PubMed1984

Interleukin 2 induction of antigen-nonspecific suppressor cells.

Although Interleukin 2 (IL-2) is essential to the generation of immune responses it may also be important as a regulator of these same responses, as both primary and secondary anti-SRBC responses are greatly diminished when IL-2 is included in culture. IL-2 must be present within the first 24 hr of culture to affect maximum suppression. This inhibition is mediated by suppressor cells which are expanded by pulsing spleen cells with IL-2 for 48-72 hr. Their development is not antigen dependent and their action is antigen nonspecific. Suppressor cell activity can be generated from either naive or primed animals which are equally effective in inhibiting primary or secondary anti-SRBC responses. Suppressor cells can be propagated for long periods of time in T-cell growth factor-containing medium. These long-term cultured cells retain the ability to inhibit various immune responses such as mitogen- and alloantigen-induced proliferation, the generation of cytotoxic T lymphocytes and humoral responses. These cells suppress these responses by absorbing IL-2, as demonstrated by their ability to remove IL-2 upon incubation at 4 degrees C, and the reversal of suppression by the addition of supraoptimal amounts of IL-2.

Animals↗
PubMed1984

C3d-K, a kallikrein cleavage fragment of iC3b is a potent inhibitor of cellular proliferation.

The C3d-K fragment generated from human iC3b by plasma kallikrein is a potent suppressant of cellular proliferation. Originally characterized as inhibiting human and murine T lymphocyte function, C3d-K is shown in these studies to suppress mitogen-induced B cell growth, the spontaneous proliferation of several tumor cell lines, as well as all forms of T cell proliferation, including that induced by interleukin 2 (IL 2). In addition, synthesis of IL 2 in mixed lymphocyte cultures is blocked by C3d-K, but not IL 2 synthesis induced by Con A. The C3d-K fragment has no effect on resting cells; however, sensitivity to the inhibitory effect of C3d-K is acquired during the activation process. Because the proliferation of mitogen-activated spleen cells is not inhibited by exposure to C3d-K for the initial 24 hr of culture, only late steps in the cell activation process are C3d-K sensitive. When C3d-K is present throughout the course of the 72-hr culture, suppression was observed. Data obtained with the tumor cell lines suggest that once suppression is achieved, it is long-lasting even in the absence of C3d-K.

Animals↗
PubMed1983

Identification and partial purification of a B cell growth-promoting material utilizing the BCL1 cell line.

A B cell growth-promoting factor (BCGF) can be detected in the culture supernatants of activated murine and human spleen cells, human peripheral blood lymphocytes, and a murine thymoma cell line by the use of the B cell leukemic cell line BCL1, which is induced to proliferate in response to this factor. Although this BCGF stimulates BCL1 cells to proliferate, it is not mitogenic for resting B cells but synergizes with dextran sulphate to induce proliferation of the latter cells. This factor has no T cell-replacing activity in an antibody response. BCGF co-purifies with interleukin 2 (IL 2) by gel chromatography and isoelectric focusing but can be separated by phenyl-Sepharose chromatography.

Animals↗
PubMed1983

Anaphylatoxin-mediated regulation of the immune response. II. C5a-mediated enhancement of human humoral and T cell-mediated immune responses.

C5a derived from the fifth component of human complement was found to potentiate both specific and non-specific human in vitro humoral immune responses. In addition, C5a is capable of potentiating antigen- and alloantigen-induced T cell proliferative responses. In contrast to these results, C5a was unable to modulate mitogen-induced B and T cell proliferative responses. The carboxyterminal arginine of C5a is not essential in order for C5a to enhance immune responses. C5ades Arg was found to augment the immune response to the level of C5a-mediated enhancement. The serum carboxypeptidase inhibitor, 2-mercaptomethyl-5-quanodinopentanoic acid, which prevents cleavage of the terminal arginine, allowed us to assay the effects of C5a on in vitro immune responses in the presence of serum. Helper T cells are involved in C5a-mediated immuno-potentiation. Substitution of T cells by soluble T cell-replacing factors, (Fc)TRF, rendered lymphocyte cultures refractory to the enhancing properties of C5a.

Adult↗
PubMed1982

Role of Fc receptors in lymphocyte activation: deficiency in T- and B-lymphocytes from aged animals.

Fc fragments derived from human immunoglobulin possess the ability to induce B-cell proliferation, polyclonal antibody responses, and augment cell-mediated and T-dependent humoral responses. However, aged animals display much lower responses to Fc fragment stimulation. Proliferation and polyclonal antibody synthesis are reduced two-five-fold in aged animals compared to the young-adult responses. Furthermore, Fc fragments are unable to potentiate plaque-forming cell (PFC) development in aged animals. Aged B-lymphocytes are deficient in responding to Fc fragments, as their admixture with young-adult T-cells does not restore polyclonal antibody formation. T-cells from aged animals are also ineffective in promoting the polyclonal response when mixed with young-adult B-cells. The T-cell lesion has been further defined as a deficiency in production of an Fc fragment induced T-cell-replacing factor [(Fc)TRF]. The inability of Fc fragments to potentiate anti-SRBC responses in aged animals is also due to a T-cell defect which can be corrected by supplementation with interleukin-2 (IL-2).

Aging↗
PubMed1982

Cell-mediated immunity in aged mice: an underlying lesion in IL 2 synthesis.

It is well established that immune potential declines with age and that aged animals are unable to mount vigorous cell-mediated immune responses. Production of the lymphokine, Interleukin 2 (IL 2) in response to the T cell mitogen concanavalin A or allogeneic stimulation is also diminished in aged individuals. This lesion in IL 2 synthesis in aged mice underlies their deficiency in cell-mediated responses. Mixed lymphocyte responses, cell-mediated lympholysis, and antigen-induced T cell proliferation are all markedly enhanced by supplementation with this lymphokine.

Aging↗
PubMed1982

Preliminary chemical and biologic characterization of (Fc)TRF: an Fc fragment-induced T cell-replacing factor.

Fc fragment stimulation of Lyt-1+2- T lymphocytes triggers release of a T cell-replacing factor, here called (Fc)TRF. Chemical and biologic characterization of (Fc)TRF has been undertaken to provide information for its comparison with other T cell factors. Preliminary chemical characterization by column chromatography and isoelectric focusing suggest (Fc)TRF activity resides in a class of acidic molecules that fall into two size classes of 58-60,000 daltons and 35-40,000 daltons. This factor is distinct from Interleukin 2 (IL 2) as it has no T cell growth-promoting or costimulator activity, although it can also be generated by Con A activation of murine spleen cells. By these results (Fc)TRF has been defined as a unique T cell-replacing activity that promotes differentiation of B lymphocytes to antibody-secreting cells.

Animals↗
PubMed1981

Enhancement of T lymphocyte functions by Fc fragments of immunoglobulins. I. Augmentation of allogeneic mixed lymphocyte culture reactions requires I-A- or I-B-subregion differences between effector and stimulator cell populations.

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.

Animals↗
PubMed1981

Lymphokines and aging: interleukin-2 production and activity in aged animals.

The capacity of aged animals to produce and respond to the T cell-replacing factor, interleukin-2 (IL-2), has been examined. IL-2 activity in the supernatants of concanavalin A-activated aged spleen cells is 5- to 10-fold lower than comparable supernatants prepared using young spleen cells. This lesion in IL-2 synthesis may limit antibody production to T-dependent antigens, because supplementation with purified IL-2 markedly enhances the number of anti-SRBC plaques generated by aged spleen cells. The response of aged splenocytes can be fully restored to that obtained using young adult cells. However, there appears to be a defect in the ability of aged cells to effectively translate the IL-2 signal into B cell helper activity, in the absence of T lymphocytes. That is, although young adult, nylon wool-purified T cells can interact with aged T-depleted spleen cells, producing a normal high level anti-SRBC response, IL-2 is incapable of reconstituting the response in aged animals to this level. On the other hand, both young adult T cells and IL-2 can interact with young adult T-depleted splenic lymphocytes to produce a normal, high level anti-SRBC response.

Aging↗
PubMed1981

Enhancement of T. lymphocyte functions by Fc fragments of immunoglobulin. II. Augmentation of the cell-mediated lympholysis response occurs through an Lyt-1+2- helper T cell.

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.

Adjuvants, Immunologic↗