Biomedical subjects

A N Schweitzer

Publications and source records attributed to A N Schweitzer.

16 recordsLinked to original sources

PubMed1999

Mutual regulation between B7-1 (CD80) expressed on T cells and IL-4.

We have used T cells from B7-1-deficient TCR transgenic DO11.10 mice to demonstrate a functional role for B7-1 on T cells. B7-1-deficient DO11.10 T cells produce more IL-4 than wild-type DO11.10 T cells, suggesting that B7-1 expressed by T cells regulates the differentiation of IL-4-producing cells. In addition, we found that IL-4 inhibits B7-1 expression by wild-type DO11.10 T cells. Our results suggest that there is a reciprocal relationship between B7-1 expressed on T cells and IL-4 production, which results in a modulatory feedback loop. When high levels of IL-4 are produced by T cells, B7-1 expression by T cells is inhibited, which allows amplification of IL-4 production by these T cells. When low levels of IL-4 are produced by T cells, B7-1 expression by these T cells is increased, and a further reduction in IL-4 production follows. However, in addition to being influenced by IL-4, B7-1 expression by T cells is affected by peptide concentration and by B7 costimulation from APCs. The studies presented here demonstrate that B7-1 on T cells as well as on APCs regulates IL-4 production. However, whereas B7-1 expression on APCs can promote IL-4 production, IL-4 production is inhibited by B7-1 on T cells.

Amino Acid Sequence↗

PubMed1998

Studies using antigen-presenting cells lacking expression of both B7-1 (CD80) and B7-2 (CD86) show distinct requirements for B7 molecules during priming versus restimulation of Th2 but not Th1 cytokine production.

The differentiation of CD4+ T cells into a Th1 vs Th2 phenotype profoundly influences the outcome of autoimmune and infectious diseases. B7 costimulation has been shown to affect the production of both Th1 and Th2 cytokines, depending on the system studied. There is, consequently, great interest in manipulating the B7 costimulatory signal for therapeutic purposes. To optimally manipulate this key immunoregulatory pathway, the contribution of B7 costimulation to cytokine production requires further clarification. We have compared the B7 requirement for cytokine production by naive vs previously activated T cells using DO11.10 TCR transgenic CD4+ T cells and splenic APCs from mice lacking B7 expression. Our data indicate that induction of IL-4 production and Th2 differentiation by naive T cells is highly dependent on B7 molecules, whereas IL-4 production by previously activated T cells is B7 independent. The predominant contribution of B7-mediated signals to Th1 cytokine production by both naive and primed T cells is upon IL-2 production (and expansion) rather than IFN-gamma (effector cytokine) production. Thus, our studies demonstrate that the antigenic experience of a T cell at the time of B7 blockade may determine whether blockade predominantly affects T cell expansion, differentiation, or effector cytokine production. These differential effects of B7 costimulation on IL-2 vs IFN-gamma production and on IL-4 production by naive vs primed T cells have important implications for understanding how B7:CD28/CTLA4 blockade can be effectively used to manipulate cytokine production in vivo.

Amino Acid Sequence↗

PubMed1998

The complexity of the B7-CD28/CTLA-4 costimulatory pathway.

There have been significant recent advances in our understanding of the role of the B7-CD28/CTLA-4 costimulatory pathway in T-cell activation and self-tolerance. Recent studies have begun to clarify how signaling through this pathway can influence cytokine production. The critical role for CTLA-4 in regulating T-cell activation and autoreactivity has been demonstrated, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. In vivo studies indicate the therapeutic potential of manipulating this important, but complex, immunoregulatory pathway.

Abatacept↗

PubMed1998

The role of B7 co-stimulation in activation and differentiation of CD4+ and CD8+ T cells.

The functional significance of B7 co-stimulation in T-cell activation was described first in the context of preventing the induction of anergy. The functions of this pathway are far more complex than initially appreciated in view of the existence of two B7 molecules which have specificities for both CD28 and CTLA-4, which serve to amplify and terminate T-cell responses respectively. Mice lacking B7 co-stimulators and CD28 and CTLA-4 co-stimulatory receptors are helping to clarify the functions of this key immunoregulatory pathway. In this review we will focus on the role of B7 co-stimulation in the activation and differentiation of CD4+ helper cells and CD8+ cytotoxic cells. The contribution of B7 co-stimulation to CD4+ responses depends upon the activation history of the T-cell and the strength of the T-cell antigen receptor signal. B7 co-stimulation contributes to interleukin (IL)-2 production by both naive and previously activated CD4+ T cells. B7 co-stimulation is most critical for the differentiation of naive CD4+ T cells to IL-4 producers, but predominately influences IL-2 production by previously activated CD4+ cells. B7 co-stimulation is important in development of cytotoxic T cells through both effects on T-helper cells and by direct co-stimulation of CD8+ cells.

Animals↗

PubMed1997

Functional consequences of dysregulated B7-1 (CD80) and B7-2 (CD86) expression in B or T lymphocytes of transgenic mice.

T cell activation and tolerance are regulated by interactions between CD28 or CTLA-4 on T cells and B7 costimulatory molecules on APCs. We have generated transgenic mouse strains that constitutively express B7-1 (CD80) at high levels on B cells or T cells or express B7-2 (CD86) on T lymphocytes to examine the consequences of dysregulated B7 expression on T cell responses. The transgene-derived B7 molecules are functional, because B7-1 transgenic B cells are more efficient APCs than are wild-type B cells, and the activation of B7 transgenic T cells is less dependent on exogenous costimulation than that of wild-type T cells. In vivo, constitutive expression of B7 molecules leads to the elimination of immature B cells. The expression of B7 molecules on thymocytes results in the down-regulation of CD28 expression. However, B7 transgenic mice have normal numbers of mature lymphocytes and mount normal T cell responses following immunization with protein Ag. Neither anergy induction nor superantigen-mediated deletion of T cells is altered by the dysregulated expression of B7-1 or B7-2 on B or T lymphocytes in these transgenic strains. Therefore, functionally significant levels of B7 expressed constitutively on mature lymphocytes are not, by themselves, sufficient to abrogate T cell tolerance or induce autoimmune disease.

Animals↗

PubMed1997

Role of costimulators in T cell differentiation: studies using antigen-presenting cells lacking expression of CD80 or CD86.

For T cells to be optimally activated, recognition of Ag/MHC complexes by the TCR must be accompanied by a second, costimulatory signal that can be provided efficiently by the related costimulatory molecules CD80 (B7-1) and CD86 (B7-2). Recently, CD80 and CD86 have been implicated as differential determinants of Th1- vs Th2-type cytokine profiles. However, this remains a controversial issue since conflicting results have been obtained in different experimental models both in vivo and in vitro. To investigate the role of CD80 and CD86 in Th subset differentiation, we have examined the cytokine profiles induced in TCR transgenic T cells stimulated by peptide in association with splenic APCs obtained from knockout mice that selectively lack expression of either the CD80 or the CD86 molecule. Our data suggest that CD86, and to a lesser extent CD80, can make significant contributions to the production of both IL-4 and IFN-gamma. However, neither molecule plays an obligatory role in priming for the production of either effector cytokine. Furthermore, CD80 and CD86 contribute to the magnitude of T cell activation, but do not appear to selectively regulate Th1 vs Th2 differentiation.

Amino Acid Sequence↗

PubMed1997

B7-1 and B7-2 have overlapping, critical roles in immunoglobulin class switching and germinal center formation.

Humoral immune responses were characterized in mouse strains lacking either or both B7 molecules. Mice deficient in both B7-1 and B7-2 failed to generate antigen-specific IgG1 and IgG2a responses and lacked germinal centers when immunized by a number of routes and even in the presence of complete Freund's adjuvant. These results demonstrate that B7-mediated signaling plays a critical role in germinal center formation and immunoglobulin class switching in vivo. Mice lacking only B7-1 or B7-2 mounted high-titer antigen-specific IgG responses when immunized in complete Freund's adjuvant, indicating that B7-1 and B7-2 can have overlapping, compensatory functions for IgG responses. When immunized intravenously without adjuvant, B7-2-deficient mice failed to switch antibody isotypes or form germinal centers, whereas B7-1-deficient mice gave antibody responses comparable with wild-type mice. Thus, B7-2 has an important role in initiating antibody responses in the absence of adjuvant, but the induction of B7-1 by adjuvant in B7-2-deficient mice can compensate for the absence of B7-2.

Abatacept↗

PubMed1996

Costimulation and autoimmunity.

The past year has seen significant advances in our understanding of the role of the B7-CD28/CTLA-4 pathway in T cell activation and self-tolerance. Recent studies have demonstrated that CTLA-4 is a critical negative regulator of T cell activation and autoreactivity, revealing a previously unsuspected means by which costimulation is involved in the maintenance and breakdown of self-tolerance. Manipulation of this costimulatory pathway in animal models of autoimmunity has shown an important role for this pathway in both the initiation and progression of autoimmune diseases.

Animals↗

PubMed1995

Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.

The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.

Abatacept↗

PubMed1994

Two signal activation as an explanation of high zone tolerance: a mathematical exploration of the nature of the second signal.

Much work on the induction of non-responsiveness in lymphocytes suggests that it takes two signals to activate a cell correctly, and that receipt of the first signal alone not only causes suboptimal response, but also subsequent non-responsiveness or anergy. This paper discusses not anergy, but the original suboptimal response in the context of the well known but poorly understood phenomenon of high zone tolerance in experiments studying immunological responses to a range of antigen concentrations (low to high "zones"). We proceed to ask specific questions about the nature and timing of the signals involved. We construct three different models describing how the second signal might be received and use them to predict the shapes of dose-response curves. Comparison with data enables us to select, from a dynamical perspective, the most likely mechanism and to tentatively exclude a number of proposed mechanisms for high zone tolerance. We suggest that the stage at which a cell becomes susceptible to anergy is crucial and that it is over-contact, rather than lack of contact, which is important in the induction of tolerance.

Antigens↗

PubMed1993

Dynamic interaction between Leishmania infection in mice and Th1-type CD4+ T-cells: complexity in outcome without a requirement for Th2-type responses.

The interaction between Leishmania parasites and Th1 cells is investigated using a simple mathematical model of immunological responses and parasite population growth within the host. The model generates patterns of resistance and susceptibility to infection that mirror observed trends in experimental infections of mice and of humans exposed to infection in areas of endemic transmission. The heterogeneity in outcome predicted by the model can arise either through differences in the values of the parameters that characterize the genetic background of the host or as a consequence of differences in the size of the infecting inoculum of the parasite. Detailed analyses of equilibrium states and of the time course of infection within a host suggest that a limitation in the availability of precursor T-cells, as a consequence of high levels of recruitment into the activated pool, may play a significant role in the progression of infection in susceptible hosts. A brief discussion is presented of the implications of model prediction for therapeutic intervention.

Animals↗

PubMed1993

CD4+ T-cell dynamics and host predisposition to infection.

Resistance to infection is often associated with proliferative T-cell responses corresponding to activation of the Th1 CD4+ T-cell subset, while the proliferative responses of chronically infected individuals are often limited. A mathematical model of the interaction between Th1 cells and a replicating pathogen has been used to demonstrate that antigen dose-dependent inhibition of Th1-cell proliferation may differentially predispose the host to resistance or chronic infection according to the level of exposure. Furthermore, the rapidity of pathogen turnover dramatically influences the qualitative relationship between exposure level and outcome, the temporal progression of infection, and the extent to which superimposed regulation of effector function (distinct from proliferation) will alter the predicted predisposition.

Antigens, Protozoan↗

PubMed1992

The regulation of immunological responses to parasitic infections and the development of tolerance.

It is well established that specific unresponsiveness to immunization can be induced by prolonged exposure to antigenic proteins. More generally, many parasitic infections, such as the helminth worms and the Leishmania parasites, appear to be able to persist in some of their human hosts over long periods of time, via what appears to be an ability to induce defective or inappropriate T-cell responses (= tolerance). Recent research has suggested that cytokines, produced by specific subsets of CD4+ T-cells (characterized by cytokine secretory profiles and growth properties), have an important, and often complex, role in promoting or inhibiting host protective immunity to parasitic infections. By examination of the population dynamics of the stimulation and regulation of cellular responses to infection, via the use of simple mathematical models, we show that nonlinear interactions between CD4+ T-cell subsets and their secreted cytokines can result in either host protection or immunological unresponsiveness, depending on the magnitude and duration of exposure to parasitic infection. Analyses also identify a possible mechanism to explain the stimulation of two separate peaks of enhanced T-cell-mediated responses over a wide range of levels of antigenic exposure.

Animals↗

PubMed1992

Dynamic interaction between CD4+ T cells and parasitic helminths: mathematical models of heterogeneity in outcome.

Potential mechanisms of immunoregulation have been investigated for the capacity to generate heterogeneity in the outcome of infection with helminth parasites. We have developed a mathematical model of the interaction between T cell and parasite populations, based on the assumption that activation of a Th1 CD4+ T cell response is required for host resistance. Antigen dose-dependent inhibition of Th1 cell proliferation generates heterogeneity in the outcome of host response to infection, with relatively low levels of exposure inducing resistance, and high levels of exposure associated with host susceptibility. Heterogeneity is additionally predicted in the duration of infection before individuals of the resistant class clear infection, with infection becoming more prolonged as the level of exposure rises. Similar categories of response are predicted if an alternative regulatory mechanism, that of interferon gamma-regulated control of Th1 cell differentiation, is substituted into the model. However, the relationship between level of exposure and duration of infection is reversed. Results are discussed in the context of how these simple models of parasite-immune system interactions might be used to make predictions concerning specific examples of parasitic infection.

Animals↗

PubMed1992

Alternative patterns of MHC-restricted antibody responsiveness following intraperitoneal immunization of inbred mice with different preparations of an 86 kilodalton antigen of Schistosoma mansoni.

The investigation of MHC restricted antibody responses to an 86 kDa antigen (p86) during chronic Schistosoma mansoni infection has been extended to immunization with this antigen. In the absence of adjuvant, a similar pattern of responsiveness by mice expressing H-2k and H-2d but not H-2b was observed following immunization with unpurified adult worm homogenate. Adjuvant selectively abrogated the capacity of H-2d mice to respond and this was also the case when purified p86 with adjuvant was injected. Immunization with purified subfragments of p86 again demonstrated MHC restriction in the capacity to immunoprecipitate p86 in vitro translation product, the pattern varying according to the fragment used. Western blot analysis showed that in some, but not all instances of apparent 'non-responsiveness' characterized by immunoprecipitation, antibody specificities capable of recognizing p86 epitopes on the nitrocellulose bound p86 were, indeed, present. Thus the fine specificity as well as the absolute capacity to respond is influenced by both the MHC haplotype of the host and the nature of the immunizing antigen.

Adjuvants, Immunologic↗

PubMed1991

MHC-restriction of antibody responses to an 86 kilodalton antigen of Schistosoma mansoni.

The previously observed MHC-restriction of the antibody response to an 86kDa S. mansoni antigen has been investigated in more detail. The I-A locus of the H-2 complex has been implicated as conferring responder or non-responder status on mice expressing the k and b alleles respectively. Inheritance of responsiveness was dominant over non-responsiveness. An additional level of complexity was observed in the p86 antibody responder status of individuals within a responding inbred strain. This could not be accounted for directly by the level of patent infection, but showed an inverse correlation with the level of egg output in H-2k mice. Differential antibody responsiveness to other antigens, between individuals of the same strain, occurred independently of the differential responsiveness to p86.

Animals↗