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G W Siskind

Publications and source records attributed to G W Siskind.

At least 19 recordsLinked to original sources
PubMed1991

Memory T cells enhance the expression of high-avidity naive B cells.

The secondary immune response classically differs from the primary response in magnitude, avidity, and isotype of the antibodies produced. Cell transfer studies to assess the contribution of memory B and memory T cells to each of these parameters are described. Avidities of the anti-DNP plaque-forming cells (PFC) generated in lethally irradiated recipients of naive B cells and keyhole limpet hemocyanin (KLH)-primed T cells, followed by immunization with soluble DNP-KLH, are medium to high, and do not differ significantly from the avidities of anti-DNP PFC in recipients of DNP-primed B cells and KLH-primed T cells. However, the number of indirect (I)-PFC and the ratio of I-PFC to direct (D)-PFC are significantly greater in the recipients of primed B and primed T cells. The results suggest that carrier primed T cells can selectively activate virgin B cells which are committed to produce medium- and high-avidity antibodies, and/or enhance the generation of somatic mutation which leads to antibodies of higher avidity. Priming of B cells is necessary for the increased magnitude of the I-PFC.

Animals↗
PubMed1990

Cellular control of IgE induction by a polyphenol-rich compound. Preferential activation of Th2 cells.

The polyphenol group rutin (R) appears to influence isotype expression, because R-BSA conjugates induce anti-BSA responses in mice that show a significant decrease in hemagglutinating antibodies (HA) to BSA, as compared to mice immunized with BSA. However, the level of IgE antibodies to BSA is unaltered. To determine if suppressor cells for isotypes other than IgE are induced by R-BSA, cell transfers were performed. The results were consistent with the view that the decrease in HA titer to BSA in R-BSA immunized mice is not due to the activation of suppressor cells for isotypes other than IgE. Inasmuch as the IgE response in mice is associated with the production of IL-4 by Th2 cells, we analyzed the factors produced by spleen cells cultured with R-BSA. We found that supernatant from spleen cells cultured with R-BSA contained IL-4 as determined by the enhanced expression of Fc epsilon R (CD23) on B cells. This enhancement was inhibited by 11B11, the anti-IL-4 mAb. IL-2, a product of Th1 cells, was not detected in these supernatants. Moreover, IL-4 mRNA, but not IL-2 mRNA, was detected by Northern blot analysis of RNA from spleen cells cultured with R-BSA. Taken together the data suggest that the polyphenol containing compounds preferentially activate Th2 cells, thereby favoring IgE production.

Animals↗
PubMed1990

Exposure of female mice to type II collagen reduces susceptibility to collagen-induced arthritis in offspring.

The effect of exposure of female DBA/1 mice to collagen II (CII) prior to breeding on the susceptibility of their offspring to CII-induced arthritis (CIA) was investigated. It was found that female offspring, born within 3 months after exposure of the mothers to CII, had a significantly reduced incidence of CIA, following immunization with CII. Just prior to this immunization, no anti-CII could be detected in the offspring. Offspring born more than 3 months after exposure of the mothers to CII showed no differences in susceptibility to induction of CIA, if optimal conditions for induction were used. However, when suboptimal conditions for induction of CIA were used, offspring of females that had been exposed to CII developed less severe arthritis and had a delayed onset of arthritis as compared with controls. It is concluded that exposure of female mice to CII prior to mating results in changes in the immune response to CII in the offspring, leading to a subtle decrease in susceptibility to CIA.

Animals↗
PubMed1990

T cell receptor variable gene expression: analysis in ragweed-sensitive patients during allergen exposure.

Four monoclonal antibodies (MAb) to V region determinants of the alpha/beta-chain of the T cell antigen receptor (TCR) were used, by cytofluorography, to detect discrete populations of peripheral blood T cells (PBT). Together they identify 10-15% of circulating CD3+ T cells. Each MAb is known to detect specific V regions of the beta-chain. Thus V beta 5 gene products are recognized by MAb C37, V beta 6 by OT145, V beta 8 by Ti3a, and V beta 12 by MAb S511. In previous studies, we found that the percentages of PBT detected by these MAb show little variation over time in normal individuals. In order to determine if there is a change in TCR V gene usage during an immune response to an environmental antigen, 12 atopic patients with known ragweed sensitivity by history and skin test were followed for a 6-month period encompassing the ragweed season. No shifts in V gene usage that could be correlated with the ragweed season were consistently observed. The patients could be arbitrarily divided into two groups: in group I little variation over time was observed in the T cell populations identified by the MAb used, while group II was characterized by marked variation of the same T cell populations over time. In group II individuals, the population of Ti3a+ T cells showed the most variation over time. Failure to observe shifts in PBT subpopulations, identified by expression of different TCR V regions, during exposure to an allergen to which an IgE response has been made may mean that such shifts do not occur or that they occur primarily at the tissue site of antigen exposure and not in the peripheral circulation or that they occur in T cell subpopulations not identified by the reagents used.

Adult↗
PubMed1990

Immunobiology of aging and cancer.

Although the incidence of neoplasms is increased in the elderly, some tumors appear to grow more slowly in old as compared to young patients. We have used the B16 melanoma to explore the relationship between age, T-lymphocyte function, and the rate of tumor growth. Increasing age is associated with a decreased rate of tumor growth and impaired T-cell function in C57BL/6 mice. Furthermore, when T-cell immunity in young mice is compromised by thymectomy, B16 tumor growth is decreased. Mixed cell transfer studies demonstrated that T cells from young but not old donors stimulate the growth of B16 melanoma cells in young lethally irradiated recipients. Recently, T cells from young but not old mice have been reported to produce angiogenic factors. As tumors from young mice have a richer vascular supply than in old mice, it appears that one mechanism for the age-associated decrease in B16 melanoma growth is the decreased capacity of T cells from old mice to generate angiogenic factors. However, parabiosis of young and old mice showed that local factors in old mice also limit the stimulatory influences of T cells from young mice. Novel therapeutic approaches to limit the growth of tumors might result from a greater understanding of the production of and response to angiogenic factors produced by T cells.

Aging↗
PubMed1989

Regulation of antibody secretion by hybridoma cells. II. Mechanism of idiotype-induced suppression of antibody secretion by hybridoma cells.

We have previously reported that antibody secretion by B.22 hybridoma cells can be suppressed in an MHC-restricted manner, by idiotype-specific T cells. It was shown that T cells of both helper and suppressor phenotypes are involved, and that the suppression is mediated by soluble factors. In the present paper, we have characterized the effects of T-cell-mediated suppression at the level of B.22 antibody mRNA expression and stability. Nuclear run-on analysis comparing suppressed and control B.22 cells indicates no change in the transcription rates of heavy and light chains. Northern blot analysis demonstrates that steady-state levels of heavy and light chain mRNAs are also unchanged. Thus, the suppression of antibody secretion by B.22 cells probably occurs at the levels of translation or secretion.

Animals↗
PubMed1989

Immunological studies of aging. Normal B-cell repertoire in aged mice: studies at a clonal level.

As previously reported, old mice produce lower avidity plaque-forming cells (PFC) after immunization with 2,4,6-trinitrophenyl-Ficoll (TNP-F) than do young mice. However, if spleen cells from TNP-F-immunized old mice are incubated with hapten to elute auto-anti-idiotype antibody then high avidity PFC, comparable to those in young mice, are detected. To further evaluate the effect of age on the B-cell repertoire anti-2,4,6-trinitrophenyl-bovine gamma globulin (TNP-BGG) hybridomas were prepared from young (6 to 8 weeks old) and old (18 to 24 months old) mice which had been primed and boosted with TNP-BGG. The monoclonal antibodies (MoAb's) were TNP-specific. Spleens from old and young mice were comparable with respect to the incidence of immunoglobulin-secreting hybridomas obtained, the incidence of TNP-BGG-specific hybridomas obtained, and the isotype distribution of the anti-TNP-BGG hybridomas. The avidities for TNP-BGG of the IgG1 anti-TNP-BGG MoAb's obtained from old and young donors were also comparable. The overall results thus suggest that old and young mice have similar B-cell repertoires and that differences in the antibodies produced are due to regulatory influences.

Aging↗
PubMed1989

Serum IgD levels in mice: effect of strain, age and autoimmune disease.

Serum IgD levels were studied in mice. Strain-related variability of serum IgD levels was noted, and advanced age was associated with markedly increased IgD levels in a large percentage of mice from all strains. Strains prone to spontaneously arising autoimmune disease had elevated IgD levels; in NZB mice this was already present very early after birth (one week), whereas in MRL mice the elevated serum IgD levels were first seen somewhat later (3 months). In contrast, mice with collagen type II (CII)-induced autoimmune arthritis had no increase in serum IgD. Injection of the immunomodulating agents LPS and complete Freund's adjuvant (CFA) did not have a significant effect on serum IgD levels, but IL-1 induced a significant decrease in IgD.

Adjuvants, Immunologic↗
PubMed1989

Peripheral T cells select the B-cell repertoire in old mice.

These studies have shown that the alterations in the repertoire of antibody produced by old mice is not due to an intrinsic defect in the bone marrow or in the B-lymphocyte population arising from the bone marrow but rather to a selective downregulation by auto-anti-idiotypic antibody and idiotype-anti-idiotype interactions, shifting the idiotype distribution in the peripheral B-cell population. Thus, the clonal distributions of B cells generated by bone marrow of old and young mice are very comparable. The age-related differences in antibodies expressed by young and old mice are, to a great extent, determined by the activity of a peripheral regulatory immune network. This immune cellular network operates prior to exposure to antigen, presumably on the basis of an idiotype-anti-idiotype network between T and B lymphocytes. After exposure to antigen, a network of idiotype-anti-idiotype antibody interactions also contributes to differences in the immune responses of old and young mice to foreign antigens. If the expressed repertoire of antibody reflects down-regulation of auto-anti-idiotypic antibody, comparable repertoires of B-cell clones would be expected to be recovered from old and young mice if B cells from old mice were rescued from selective peripheral downregulatory influences active in old mice. Support for this hypothesis has been obtained by generating B-cell hybridomas from young and old mice immunized with TNP bovine gamme globulin (Marcenario et al. 1989). The same number of anti-TNP hybridomas and a comparable number of IgG and high-affinity antibody-producing clones were recovered from the spleens of young and old mice. Thus, the actual B-cell clonal repertoires of young and old mice appear to be similar although the expressed repertoires of antibody-producing lymphocytes from old and young mice are very different. This conclusion has considerable impact on strategies that could be employed to reverse the senescence of humoral immunity. Strategies to counter downregulatory influences which constrain the expression of the B-cell population should be more effective than attempts to reconstitute the repertoire of B lymphocytes in aged individuals. Finally, the mechanisms underlying these age-associated shifts in the expressed humoral antibody response can be attributed to life-long interactions with self and foreign antigens. The overall shift may be described as a decreased reactivity to foreign antigens and a complementary increase in reactivity with self antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1989

Production of auto-anti-idiotype antibody during the normal immune response. XIV. Evidence for the antigen-independent operation of the idiotype network.

We have previously shown that that idiotype (Id) repertoire expressed by old mice is different from that of young mice after immunization with trinitrophenylated Ficoll. Older mice also produce more auto-anti-Id antibodies than do young mice. Mice surviving a normally lethal dose of radiation (800 rads) as result of partial shielding of their bone marrow slowly recover immune function, after the repopulation of their peripheral lymphoid system by bone marrow precursor cells. Aged mice subjected to such a procedure produce low auto-anti-Id responses, like those of young mice. However, transfer of splenic T cells from old donors into such mice increases the magnitude of the auto-anti-Id response. In the present studies, we show that the age-related shift in Id expression is also determined by the age of the donor T cells. Furthermore, we show in serial cell transfer studies that the peripheral T-cell population of old mice modifies the level of the auto-anti-Id response in the absence of antigen. The results thus provide evidence for the normal, in vivo, operation of an Id-anti-Id network between B and T lymphocytes.

Aging↗
PubMed1988

Studies on suppressor factors produced by T-cell hybridomas. I. Characterization of antigen-specific suppressor factors.

Antigen-specific and antigen-nonspecific suppressor T cells were generated when spleen cells prepared from C57BL/6J (H-2b) were incubated with trinitrophenylated polyacrylamide beads (TNP-PAA) in vitro. T hybridomas were prepared by fusion of spleen cells cultured with TNP-PAA for 4 days and the thymoma cell line BW5147. More than 100 hybridomas were generated, and 15 of them suppressed the anti-TNP PFC response of fresh spleen cells cultured with TNP-PAA. The suppression was antigen specific with three of these five hybridoma supernatants tested. Hybridomas that caused antigen-specific suppression secrete factors which bring about suppression of the anti-TNP PFC response by spleen cells cultured with TNP-PAA. These hybridoma supernatants which cause antigen-specific suppression typically depressed the anti-TNP PFC response by 60% while depressing anti-SRBC PFC response by only 10%. The antigen-specific suppressor factors were bound to a TNP-BGG column but not to a BGG column. The suppressor factors, purified by affinity chromatography on a TNP-BGG column, were bound to anti-I-Jb antibody.

Acrylic Resins↗
PubMed1988

A cross-reactive idiotype on anti-collagen antibodies in collagen-induced arthritis: identification and relevance to disease.

Immunization of mice with type II collagen (CII) leads to the production of anti-CII antibodies and, in susceptible strains, to the induction of arthritis. Specifically purified anti-CII antibodies from arthritic DBA/1 mice were used to prepare a rabbit anti-idiotypic antiserum. This antiserum recognizes a cross-reactive idiotype (CRI) present on 20-25% of anti-CII antibodies from DBA/1 mice immunized with bovine CII. The CRI is not present on DBA/1 anti-trinitrophenyl, undetectable in normal Ig and not Igh allotype linked. The presence of this CRI was examined after antigen specific suppression of the anti-CII antibody response by intravenous administration of chick or bovine CII. While intravenous injection of bovine CII, prior to immunization with chick CII, greatly reduces both the incidence of arthritis and the anti-CII response, the fraction of anti-bovine CII which expresses the CRI is increased by this treatment. These findings suggest that the CRI characterizes a disease-unrelated fraction of anti-CII which recognizes bovine and chick CII, but probably not mouse CII. In addition, attempts at idiotypic regulation of arthritis incidence and antibody response by in vivo administration of anti-idiotypic serum also indicate that the CRI-bearing antibody is not important for the induction of arthritis.

Animals↗
PubMed1979

Production of auto-anti-idiotypic antibody during the normal immune response to TNP-ficoll. III. Absence in nu/nu mice: evidence for T-cell dependence of the anti-idiotypic-antibody response.

Although athymic mice make an excellent immune response to the thymus-independent antigen trinitrophenyl-lys-Ficoll (TNP-F), nude mice of AKR/J and BALB/c strains lack the anti-idiotypic response that occurs in euthymic mice of both of these strains within the first 1--2 wk after injection of more TNP-F. Anti-idiotypic antibody-blocked (hapten-augmentable) anti-TNP splenic plaque-forming cells (PFC) do not occur at any time and serum anti-idiotypic antibody is absent in both congenitally athymic mice, and thymectomized, irradiated, bone marrow-reconstituted mice. Nevertheless, nu/nu mice do have PFC which can be inhibited by exposure to anti-idiotypic antibody produced in +/+ mice. As a consequence of the failure to produce anti-idiotypic antibodies, the anti-TNP PFC response is athymic as compared to euthymic mice is of greater magnitude, declines less precipitously, and shows an increase rather than a decrease in affinity between days 4 and 7 after antigen injection. It is concluded that the anti-idiotypic antibody response is thymus dependent and that athymic mice lack a helper cell required for the induction of anti-idiotypic antibodies.

Animals↗
PubMed1979

Production of auto-anti-idiotypic antibody during the normal immune response to TNP-ficoll. I. Occurrence in AKR/J and BALB/c mice of hapten-augmentable, anti-TNP plaque-forming cells and their accelerated appearance in recipients of immune spleen cells.

Attempts were made to elucidate the cause of the downward regulation of the splenic plaque-forming cell (PFC) response in AKR/J and BALB/c mice between days 4 and 7 after a single intravenous injection of 2,4,6,trinitrophenyl- lys-Ficoll(TNP-F). AKR/J spleen cells, taken 7 d after injection of TNP-F, were transferred, together with TNP-F, into normal AKR/J mice. The day-3 or - 4 PFC response of the recipients was much lower than that of recipients of normal cells. However, the suppression was only apparent because the presence of 10(-8)-10(-7) M 2,4,6-trinitrophenyl-epsilon-amino-n-caproic acid (TNP- EACA) (or 10(-7)-10(-6) M 2,4,-dinitrophenyl-epsilon-amino-n-caproic acid) in the PFC assay caused a dramatic increase in observed PFC, averaging 298 percent on day 3 and 122 percent on day 4. Recipients of normal cells showed no such hapten-augmentable PFC. T-depleted immune spleen cells did not cause any apparent suppression of the response to TNP-F, but hapten-augmentable PFC in recipient spleens were again prevalent. Suppression of the PFC response, as well as hapten-augmentable PFC, were seen after transfer of immune serum. It was postulated that hapten augmentation of PFC was caused by displacement of auto-anti-idiotypic antibody from the surface of blocked antibody- synthesizing cells. Further studies showed that such hapten-augmentable PFC occurred in the spleens of a large percentage of both AKR/J and BALB/c mice examined after day 4 of the primary response to TNP-F. Thus, it was hypothesized that the downward regulation of the magnitude and, possibly, also of the heterogeneity of the splenic-PFC response was due to an auto-antibody response to one or more major idiotypes of the anti-TNP response.

Animals↗
PubMed1979

Production of auto-anti-idiotypic antibody during the normal immune response to TNP-Ficoll. II. Hapten-reversible inhibition of anti-TNP plaque-forming cells by immune serum as an assay for auto-anti-idiotypic antibody.

Sera taken from AKR/J mice 7 d after the intravenous injection of 2,4,6-trinitrophenyl-lys-Ficoll (TNP-F) caused a specific inhibition of anti- trinitrophenol (TNP) plaque-forming cells (PFC) in vitro. This inhibition was reversed by the incorporation of 10(-8)-10(-7) M 2,4,6-trinitrophenyl- epsilon-amino-n-caproic acid (TNP-EACA) into the agar during the PFC assay. The factor responsible for the hapten-reversible PFC inhibition was removed from serum by passage through an anti-immunoglobulin column or through a 2,4,-dinitrophenyl-human-serum-albumin-bromoacetylcellulose plus anti-TNP- antibody column, but not by DNP-HSA-BAC alone. It was concluded that this immunoglobulin-like substance, lacking anti-TNP activity but reacting with anti-TNP antibody of AKR/J origin, was most likely an auto-anti-idiotypie antibody that had been produced during the normal course of the response of AKR/J mice to TNP-F. Pools of anti-idiotypic-antibody-containing antisera inhibited anti-TNP plaque formation to varying degrees when tested on d-4 PFC from different mice of the same inbred strain, suggesting a variability in idiotype expression. 4 d after transfer of immune (7 d after 10 mug TNP-F, administered intravenously) AKR/J spleen cells plus 10 mug TNP-F into syngeneic mice, the number of PFC detectable in the recipients' spleens could be markedly augmented by the inclusion of TNP-EACA in the agar during the PFC assay. Incubation of spleen cells containing such hapten-augmentable PFC with TNP- EACA yielded a factor in the supernate that caused a specific, in vitro, hapten-reversible inhibition of anti-TNP PFC. Studies with immunoadsorbents indicated that this PFC-inhibiting factor was antigenically immunoglobulin- like, lacked anti-TNP-antibody activity, but reacted with anti-TNP antibody of AKR/J origin. The results are consistent with the view that this PFC inhibitor is auto-anti-idiotypic antibody that is involved in the normal regulation of the immune response. It is proposed that hapten-reversible inhibition of plaque formation can be employed as an assay for anti-idiotypic antibody and the conditions for such an assay are described. It is further proposed that the detection of hapten-augmentable PFC suggests the presence of auto-anti-idiotypic antibody.

Animals↗
PubMed1979

Ontogeny of B-lymphocyte function. IX. Difference in the time of maturation of the capacity of B lymphocytes from foetal and neonatal mice to produce a heterogeneous antibody response to thymic-dependent and thymic-independent antigens.

The ontogeny of the capacity of the B-lymphocyte population to produce a response which is heterogeneous with respect to antibody affinity was studied in a cell transfer system. Lethally irradiated mice were reconstituted with B cells from donors of various ages, together with adult thymus cells when the response to T-dependent antigens was studied. The animals were immunized with one of a variety of antigens one day after cell transfer and the distribution of their splenic plaque-forming cells (PFC) with respect to affinity was assayed, by hapten inhibition of plaque formation, 2 to 3 weeks after immunization. Mice reconstituted with B cells from neonatal donors produced a response of low affinity and restricted heterogeneity. With four different thymic-dependent antigens (DNP-BGG, F-BGG, DNP-KLH and Dan-KLH) the splenic B-cell population acquired the capacity to reconstitute irradiated mice to produce a normal adult-like, highly heterogeneous, high affinity PFC response between 7 and 10 days after birth. The capacity to produce a heterogeneous response to the thymic-dependent protein antigen BGG matured just slightly later between 10 and 14 days of age. The bone marrow matures with regard to the capacity to reconstitute irradiated mice to give a heterogeneous response several days after the spleen, possibly as a consequence of the redistribution of peripheral B cells to the bone marrow. In contrast, maturation of the capacity of the splenic B-cell population to reconstitute irradiated recipients to give a heterogeneous, adult-like PFC response to three 'thymic-independent' antigens (TNP-PA, DNP-Ficoll and TNP-BA) takes place considerably later (between 3 and 4 weeks of age). These results suggest that the population of B-cell precursors which responds to thymic-dependent antigens may represent a different subpopulation of B cells from the population that responds to thymic independent antigens. Furthermore, the results suggest that these B-cell subsets mature at different times, presumably under independent controls.

Age Factors↗