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Biomedical subjects

D E Parks

Publications and source records attributed to D E Parks.

33 records · Page 2Linked to original sources
PubMed1981

Bacterial lipopolysaccharide (endotoxin) interferes with the induction of tolerance and primes thymus-derived lymphocytes.

The injection of deaggregated human gamma-globulin (DHGG) into mice results in the establishment of specific immunologic unresponsiveness in T and B lymphocytes. However, the additional injection of bacterial lipopolysaccharide (LPS) 3 hr later converts the tolerogenic DHGG into an immunogen for both helper T and B cells. This generation of immunocompetence to HGG during interference with tolerance induction by LPS is demonstrated by both a primary plaque-forming cell response to DHGG + LPS and a secondary antibody response to a subsequent antigenic challenge. The secondary response to antigen stimulation in the B cells is, however, T cell dependent. Interference with tolerance induction in antigen-specific helper T cells can be demonstrated by challenge with the DNP-HGG hapten-carrier conjugate or by adoptive cell transfer with primed B cells and subsequent challenge with immunogenic HGG. Furthermore, helper T cells in the spleen and thymus become primed by DHGG + LPS as evidenced by their cooperation with primed B cells in the adoptive transfer assay. In addition to its interference with tolerance induction, LPS injected with either tolerogenic or immunogenic HGG also facilitates priming of helper T cells for the response to DNP-HGG. These data indicate that exposure of antigen-specific helper T and B cells to antigen alone results in the induction of tolerance, whereas induction of immunocompetence in these cells requires at least 2 signals, 1 provided by interaction with antigen and a 2nd delivered by a nonspecific stimulus similar to that provided by LPS in the present experiments.

Adjuvants, Immunologic↗
PubMed1981

Establishment of unresponsiveness in primed B lymphocytes in vivo.

As an approach to examine the influence of the state of cellular activation on the ability to tolerize B cells, the induction of unresponsiveness in human gamma-globulin-(HGG) primed B lymphocytes was studied in an adoptive transfer system. In contrast to transferred normal spleen cells, spleen cells from HGG-primed mice are not readily rendered unresponsive when exposed to the tolerogen, deaggregated HGG (DHGG), in irradiated recipients. A kinetic study showed that unfractionated primed spleen cells do not respond to an antigenic challenge given between 6 and 10 days after cell transfer and injection of DHGG, indicating that they are transiently depressed. In contrast, isolated primed B cells are tolerized when transferred to recipients and treated with DHGG in the absence of T cells. Furthermore, primed B cells exposed to tolerogen in the recipients do not recover the ability to respond to HGG either after a secondary challenge with AHGG given up to 14 days after transfer, or after 2 consecutive challenges given on days 14 and 24 after transfer. The presence of primed T cells at the time of tolerization interferes with the induction of unresponsiveness in these primed B cells. These studies suggest that the presence of primed T cells is responsible for the inability to tolerize unfractionated primed spleen cells populations and that primed B cells themselves are not intrinsically resistant to the induction of unresponsiveness.

Animals↗
PubMed1980

Polyclonal B lymphocyte activation during Trypanosoma cruzi infection.

Infection of A/J mice with Trypanosoma cruzi results in the polyclonal activation of B lymphocytes in vivo as assessed by the spontaneous plaque-forming cell (PFC) response to trinitrophenyl and to goat, equine, and sheep erythrocytes. The peak response to these antigens is found at 5 to 6 days of infection. Additionally, a polyclonal response to syngeneic erythrocytes can be detected in infected mice by using aged but not fresh indicator cells. Polyclonally stimulated PFC to human gamma-PFC found late in infection during a period of marked splenomegaly and parasitemia. This trypanosoma-induced polyclonal B cell activation may well be responsible for the abnormalities in immunoglobulin synthesis and secretion that have been reported to occur during human infection with T. cruzi.

Animals↗
PubMed1980

Immunologic unresponsiveness after gastric administration of human gamma-globulin: antigen requirements and cellular parameters.

Gastric administration of human gamma-globulin (HGG) into adult A/J mice leads to the establishment of an antigen-specific unresponsive state to subsequent parenteral challenge with HGG. An unresponsive state is induced in both helper T and B lymphocyte populations. Unresponsiveness in helper T cells is of longer duration than in B cells, lasting at least 9 wk after intragastric intubation. Adoptive cell transfer of spleen cells from gastrically inoculated mice into healthy irradiated, syngeneic recipients revealed that the unresponsive state is stable upon cell transfer and that suppressor cells are present in the spleens of gastrically tolerized mice. The establishment of HGG-specific unresponsiveness is dependent upon both the dose and the form of the antigen adminstered. Soluble and deaggregated HGG are both more efficient than is heat-aggregated HGG in inducing unresponsiveness gastrically. The administered HGG is rapidly eliminated from the animal and only a small fraction reaches the circulation as immunoreactive protein. Although the cellular parameters of the systemic unresponsiveness induced by intragastric intubation with HGG appear similar to the parameters of parenterally induced unresponsiveness, the precise mechanisms by which gastric unresponsive states are established remain to be resolved.

Animals↗
PubMed1979

Induction and mode of action of suppressor cells generated against human gamma globulin. II. Effects of colchicine.

The ability of colchicine (Col) to interfere with suppressor cells specific for the soluble protein antigen human gamma globulin (HGG) has been examined. This interference may be the mechanism of the adjuvanticity promoted by Col. When injected into A/J mice at the appropriate time and concentration, both Col and cyclophosphamide promoted an adjuvant increase in the plaque-forming cell response to 100 micrograms of immunogenic, aggregated HGG. Col abrogated both the induction of suppressor cells when injected with 3 h of tolerization with deaggregated (DHGG) and the expression of previously induced suppressor cells when injected with the antigenic challenge. Interference with the generation and expression of antigen-specific suppressor cells had no detectable effects on the immunologic unresponsive state to HGG. Col did not interfere with the induction of tolerance at a dose (1 mg/kg) that abolished the generation of suppressor cells. Furthermore, the absence of colchicine-sensitive-suppressor cells during the establishment of tolerance had no observable effect on the duration of unresponsivness in either helper T- or B-lymphocyte populations. Finally, Col was not able to terminate the unresponsive state established by DHGG even when responsive splenic B cells could be demonstrated in tolerant animals. These data indicate that suppressor cells are not required for the establishment and maintenance of the unresponsive state to this antigen.

Adjuvants, Immunologic↗
PubMed1979

B-lymphocyte activation with an extract of Nocardia brasiliensis.

An extract from the pathogenic actinomycete Nocardia brasiliensis was mitogenic for murine lymphocytes. This deoxyribonucleic acid-synthetic response of whole spleen cells peaked after 48 h in culture at concentrations of Nocardia extract ranging from 10 to 200 micrograms/ml. The extract appeared to be a mitogen for B lymphocytes since cultures of spleen cells from congenitally athymic nude (nu/nu) mice and of antithymocyte serum plus complement-treated spleen cells from conventional (+/+) mice responded as well as untreated spleen cells from normal +/+ mice. Furthermore, thymocytes did not respond mitogenically to the extract. Mitogenic responses were stimulated in spleen cells from H-2(a), H-2(b), H-2(d), and H-2(k) mice, including lipopolysaccharide-nonresponder C3H/HeJ mice. This Nocardia extract also stimulated polyclonal B-cell activation to the hapten trinitrophenyl, serum protein human gamma globulin, and several mammalian erythrocytes in cultures of cells from both euthymic and nude mice. Additionally, the requirement for helper T cells in the primary in vitro immune response to sheep erythrocytes could be circumvented by the addition of this Nocardia extract. These results indicate that an extract from the pathogen N. brasiliensis can nonspecifically activate murine B lymphocytes and raise the possibility that polyclonal activation of B lymphocytes may contribute to the pathogenesis of nocardiosis.

Animals↗
PubMed1978

Induction and mode of action of suppressor cells generated against human gamma globulin. I. An immunologic unresponsive state devoid of demonstrable suppressor cells.

A model of unresponsiveness to human gamma-globulin (HGG) which is maintained in the absence of demonstrable suppressor cells has been described. A/J mice were tolerized with deaggregated HGG purified from a variety of sources. The spleen cells from these tolerized mice were assessed for their ability to suppress the response of normal spleen cells to HGG when transferred into lethally irradiated mice. All of the HGG preparations obtained from commercial sources as Cohn fraction II of pooled, outdated plasma induced suppressor cells to HGG, although not of equal magnitude. However, suppressor cells could not be demonstrated in the spleens of mice tolerized with deaggregated HGG purified from the plasma of a healthy individual. This inability to detect suppression was independent of the method of purification of the HGG and of the time of assessment of the putative suppressor cells after tolerization. Similarly, deaggregated HGG isolated from an IgG1 lambda-myeloma protein induced unresponsiveness to HGG but did not stimulate demonstrable suppressor cells. These data suggest that suppressor T cells are not involved in the maintenance of tolerance to this antigen, although they may play a regulatory role in the immune response to HGG. Support for this concept was obtained by assessing the duration of unresponsiveness in the T and B lymphocytes of mice tolerized with the various HGG preparations. Mice tolerized with the HGG preparations that stimulated little or no suppression were among the last to recover responsiveness. Indeed, there was no consistent correlation between the level of suppressor cell activity and the degree of unresponsiveness in either the splenic T or B lymphocytes. Thus, although certain HGG preparations may provide a tool for the generation of antigen-specific suppressor T cells, the utilization of these suppressive preparations may be inappropriate for the investigation of the mechanisms of the induction and maintenance of the unresponsive state.

Animals↗
PubMed1978

Immunologic responsiveness of the C3H/HeJ mouse: differential ability of butanol-extracted lipopolysaccharide (LPS) to evoke LPS-mediated effects.

The lipopolysaccharide (LPS)-protein complex extracted from the cell wall of Escherichia coli K235 by the butanol-water technique has been shown to evoke a mitogenic response in bone marrow-derived (B) lymphocytes from the C3H/HeJ mouse strain. These mice are resistant to the effects of LPS extracted with phenol. Therefore, the ability of butanol-extracted LPS to modulate a spectrum of C3H/HeJ B-cell functions was investigated. Both butanol-extracted (LPS-B) and phenol-extracted (LPS-P) LPS preparations activated responder C3H/St spleen cell cultures to polyclonal antibody production, while only LPS-B activated C3H/HeJ spleen cells. Both LPS-P and LPS-B acted as adjuvants when injected after aggregated human gamma globulin (HGG) in C3H/St mice, but neither preparation was effective as a adjuvant in C3H/HeJ mice. LPS-P injected with deaggregated HGG (tolerogen) into LPS-sensitive mice has been shown previously to inhibit the induction of tolerance HGG. In the present studies, it was shown that LPS-B, but not LPs-p, was able to inhibit tolerance induction to HGG in the C3H/HeJ, whereas both preparations were effective in the C3H/St. LPS has also been shown to bypass tolerant T cells in LPS-sensitive mice late in tolerance to HGG at a time when B cells are responsive. However, in the C3H/HeJ, neither LPS-B nor LPS-P was capable of this function. The responsiveness of these B cells to HGG was demonstrated in transfer experiments. Thus, in the C3H/HeJ, LPS-B stimulates mitogenesis, polyclonal B-cell activation, and inhibition of tolerance induction, but cannot act as an effective adjuvant or as a bypass mechanism to activate B cells in the presence of tolerant T cells. The explanation for this pattern of responses may be attributable to yet another cellular defect in the C3H/HeJ mouse.

Adjuvants, Immunologic↗
PubMed1978

Effect of aging on immune and tolerant states.

A model has been described for studying the effect of aging on the cellular events involved in the induction, maintenance, and termination of a central tolerant state representative of the natural tolerant state to self. This model may permit an approach to the examination of the immune status of subpopulations of T and B cells to self antigens during aging. Prelminary data with NBZ mice, which show signs of accelerated autoimmune disease, suggest a possible defect detected by changes in polyclonal activation of B cells. This defect appears to be at the B cell level and not to involve suppressor T cells.

Aging↗
PubMed1976

Specific suppression of the immune response by HGG tolerant spleen cells. I. Parameters affecting the level of suppression.

After adoptive transfer, the spleen cells from mice made tolerant to human gamma-globulin (HGG) specifically suppress the immune response of normal spleen cells. However, this suppressive activity in the spleen cells of tolerant mice is only present for a brief period after treatment with tolerogen. Spleen cells from animals injected 10 days earlier with tolerogen reduce the immune response of an equal number of normal spleen cells by 75%. Spleen cells from mice made tolerant 40 days previously are, however, no longer suppressive, even though they remain completely unresponsive. These data suggest that active suppression of antigen-reactive cells is not the mechanism responsible for maintaining tolerance to HGG, but rather is only transiently associated with the tolerant state. Further evidence in favor of the separation of the tolerant state from suppressive activity is that complete suppression of the normal spleen cell response requires either a high ratio of tolerant to immune competent cells or a delay in the antigenic challenge of the reconstituted recipients. By contrast, such manipulations are not required to demonstrate the complete unresponsiveness of the tolerant cells after adoptive transfer.

Animals↗