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Biomedical subjects

W Stohl

Publications and source records attributed to W Stohl.

At least 19 recordsLinked to original sources
PubMed2004

Raised levels of anti-glucose-6-phosphate isomerase IgG in serum and synovial fluid from patients with inflammatory arthritis.

BACKGROUND: In K/BxN mice, anti-glucose-6-phosphate isomerase (GPI) antibodies (Abs) are arthritogenic, and their transfer into naive mice induces arthritis. Anti-GPI Abs develop in many human patients with RA and are associated with more severe forms of the disease. OBJECTIVE: To elucidate the serum and synovial fluid (SF) anti-GPI IgG profiles among different patient groups with a variety of arthritides. METHODS: Blood and SF obtained concomitantly from 91 patients with clinically well defined arthritis were tested for concentrations of total anti-GPI IgG, anti-GPI IgG subclasses, B lymphocyte stimulator (BLyS), and APRIL by ELISA. RESULTS: Anti-GPI IgG was detected in sera and SF of patients with many arthritic diseases, but was preferentially associated with inflammatory arthritis, in general, and RA, in particular. The anti-GPI IgG subclass usage was skewed and varied among the different arthritic disease groups. Inverse correlations between serum levels of BLyS and anti-GPI IgG and positive correlations between serum levels of APRIL and anti-GPI IgG were seen among immune based arthritic patients and patients with RA but not among non-immune based patients. No correlations were found in SF from any group of arthritic patients. CONCLUSION: Raised circulating anti-GPI Abs are not unique to patients with RA but are present in many patients with inflammatory arthritis. The difference in anti-GPI IgG subclass usage among disease groups may influence effector function and disease outcome. The inverse correlation between serum BLyS and anti-GPI IgG levels suggests that anti-GPI B cells may be regulated differently from other autoantibody producing B cells. Anti-GPI Abs may serve a pathogenic function in humans by promoting the maintenance of existing disease.

Adult↗
PubMed2004

Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus.

OBJECTIVE: To assess longitudinal expression of a proliferation-inducing ligand (APRIL) in patients with systemic lupus erythematosus (SLE) and its correlation with B lymphocyte stimulator (BLyS) expression, serum anti-dsDNA titres, and clinical disease activity. METHODS: Sixty eight patients with SLE were longitudinally followed up for a median of 369 days. At each visit the physician assessed disease activity by SLEDAI, and blood was collected for determination of serum APRIL and BLyS levels and of blood APRIL and BLyS mRNA levels. Fifteen normal control subjects underwent similar laboratory evaluation. RESULTS: Dysregulation of APRIL was not as great as that of BLyS. Changes in serum levels of APRIL and BLyS over time were usually discordant, whereas blood levels of APRIL and BLyS mRNA strongly paralleled each other. Serum APRIL levels modestly, but significantly, inversely correlated with serum anti-dsDNA titres in anti-dsDNA positive patients analysed in aggregate. Moreover, serum APRIL levels modestly, but significantly, inversely correlated with clinical disease activity in all patients analysed in aggregate. CONCLUSION: Serum levels of APRIL and BLyS are differentially regulated. APRIL may serve as a down modulator of serological and/or clinical autoimmunity in patients with SLE. This may have important ramifications for BLyS targeted treatment, and it remains to be determined whether agents which neutralise only BLyS will be preferable to agents which neutralise both BLyS and APRIL.

Antibodies, Antinuclear↗
PubMed2004

A therapeutic role for BLyS antagonists.

B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice may lead to systemic lupus erythematosus (SLE)-like disease, and treatment of bona fide SLE mice with BLyS antagonists ameliorates disease progression and enhances survival. BLyS overexpression is common in human SLE, and results from a phase I clinical trial with a BLyS antagonist in human SLE have shown the antagonist to be biologically active and safe. These features collectively point to BLyS as an attractive therapeutic target in human disease.

Animals↗
PubMed2001

Cell cycle phase-specific survival of CD95 ligand-challenged Jurkat cells: upregulation of heat-shock response.

An important means of regulating T-cell function occurs via physical deletion (cytolysis) of unnecessary/unwanted T cells. Among cytolytic pathways, CD95 (Fas)-based killing plays a prominent role. Although activation of T cells results in rapid upregulation of surface CD95 expression, sensitivity to CD95-based killing lags behind. To assess determinants of resistance to CD95-based killing, we used Jurkat cells as a model. Analysis of the 10% survivors of a LD(90) dose of CD95 ligand (CD95L) at 24 h demonstrated them to arise preferentially from the S + G2/M phases of the cell cycle and to remain clustered in S + G2/M without undergoing cell division. Protein immunoblot, immunocytochemistry, and RT-PCR analyses demonstrated that hsp72 was markedly upregulated in CD95L survivors within hours of CD95L challenge, indicative of a heat-shock response. Indeed, exposure of Jurkat cells to bona fide heat shock did markedly upregulate hsp72 and, upon subsequent CD95L challenge, did greatly enhance cell survival with persistent clustering to S + G2/M. These findings collectively suggest that in response to a CD95L insult, development of a heat-shock response above some critical threshold level can protect against lethality. This raises the possibility that exaggerated and/or protracted heat-shock responses under in vivo conditions may favor the survival of T cells (including autoaggressive T cells) that otherwise would be destined to die via a CD95-based pathway.

Apoptosis↗
PubMed2001

Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases.

OBJECTIVE: To determine whether serum levels of B lymphocyte stimulator (BLyS) are elevated in patients with systemic immune-based rheumatic diseases and correlate with serum Ig levels and/or autoantibody titers. METHODS: Sera from 185 patients with various systemic immune-based rheumatic diseases (95 with systemic lupus erythematosus [SLE], 67 with rheumatoid arthritis [RA], 23 with other diagnoses) were assayed for BLyS and Ig. In 7 patients who required arthrocentesis of a swollen knee, coincident serum and synovial fluid samples were assayed for BLyS. Medical charts were retrospectively reviewed for elevated autoantibody titers and proteinuria within a 1-month period before or after collection of sera for BLyS and Ig determination. Sera concurrently collected from 48 normal healthy subjects served as controls. RESULTS: Serum BLyS levels were elevated in 38 of 185 patients (21%) and correlated significantly with serum IgG levels. Serum BLyS levels did not correlate with the patients' age, sex, race, or medications, but correlated positively with anti-double-stranded DNA antibody titers among SLE patients and with rheumatoid factor titers among seropositive RA patients. In contrast, serum BLyS levels correlated inversely with nephrotic-range proteinuria among SLE patients. In every case tested, BLyS levels in clinically inflamed synovial fluids were greater than those in simultaneously obtained sera. CONCLUSION: BLyS may be an important factor in driving polyclonal hypergammaglobulinemia and elevated autoantibody titers in patients with systemic immune-based rheumatic diseases. Local production of BLyS in the joints may contribute to joint pathology. Patients with elevated serum BLyS levels may be ideal candidates for therapeutic targeting of BLyS.

Adolescent↗
PubMed2001

In vivo staphylococcal superantigen-driven polyclonal Ig responses in mice: dependence upon CD4(+) cells and human MHC class II.

Staphylococcal enterotoxin (SE) B and seven other staphylococcal superantigens (SAg), despite promoting vigorous Ig production in human peripheral blood mononuclear cell cultures, are exceedingly poor at eliciting Ig responses in cultures of spleen cells from C57BL/10J (B10) or C3H/HeJ mice. In contrast, SEB elicits Ig responses in cultures of spleen cells from human MHC class II-transgenic mice. Whereas i.p. administration of SEB (0.2-20 microg) to non-transgenic B10 mice elicits very weak in vivo Ig responses, identical treatment of CD4(+) cell-intact (but not CD4(+) cell-depleted) human MHC class II-transgenic mice elicits dramatic increases in both splenic Ig-secreting cells and serum Ig levels. Over a 2-week period, the SEB-induced in vivo Ig responses peak and then plateau or fall in association with a preferential increase in splenic CD8(+) cells. Nevertheless, in vivo depletion of CD8(+) cells has no sustained effect on SEB-driven Ig responses. Taken together, these observations demonstrate that the effects of SAg on in vivo humoral immune responses are highly CD4(+) cell dependent, are substantially CD8(+) cell independent and can be successfully investigated using human MHC class II-transgenic mice. This model system may be useful in investigating the polyclonally activating effects of microbial products (prototypic environmental insults) on the development of systemic autoimmunity.

Animals↗
PubMed2000

Promotion of activated human B cell apoptosis and inhibition of Ig production by soluble CD95 ligand: CD95-based downregulation of Ig production need not culminate in activated B cell death.

CD95/CD95L interactions are vital to normal lymphoid homeostasis and in the protection against autoimmunity. To directly assess the effects of CD95L on activated B cell survival and Ig responses, purified human peripheral blood B cells, activated in vitro with SAC + rIL2, were incubated with a soluble CD95L fusion protein (fp) and assayed for apoptosis and IgG/IgM production. CD95L fp reproducibly increased apoptosis of these activated B cells and inhibited their Ig production. However, CD95L fp-mediated effects on activated B cell survival could be uncoupled from those on Ig production in that a soluble CD40L fp was incapable of reversing CD95L fp-mediated downregulation of Ig responses despite inhibiting CD95L fp-mediated apoptosis. Moreover, despite the specific caspase-8 inhibitor z-IETD-fmk substantially protecting transformed CL-01 B cells from CD95L fp-mediated apoptosis and permitting their ongoing proliferation, caspase-8 inhibition had no protective effects on CD95L fp-mediated inhibition of constitutive IgM production by CL-01 B cells. Collectively, these results point to a CD95-based downregulatory pathway in activated B cells that need not necessarily culminate in their death.

ADP-ribosyl Cyclase↗
PubMed1999

Impaired cytotoxic T lymphocyte activity in systemic lupus erythematosus following in vitro polyclonal T cell stimulation: a contributory role for non-T cells.

To determine whether non-T cells contribute to impaired generation of nonrestricted cytotoxic T lymphocyte (CTL) activity in human SLE, peripheral blood mononuclear cells (PBMC) and sort-purified T cells from normal subjects and SLE patients were stimulated with anti-CD3 mAb, maintained in IL2, and assayed for cytolytic activity against 51Cr-labeled Daudi target cells. In addition, T cell and non-T cell fractions were isolated from nine pairs of monozygotic (MZ) twins discordant for SLE, reconstituted in a criss-cross pattern, and stimulated and assayed for cytolytic activity. Cytolytic responses were significantly lower in SLE PBMC cultures than in normal PBMC cultures. Addition of SLE serum to normal PBMC cultures did not inhibit generation of normal cytolytic responses, and neither 'resting' SLE PBMC prior to stimulation nor addition of neutralizing anti-IL10 mAb or costimulating anti-CD28 mAb restored generation of SLE cytolytic responses to normal. Nevertheless, despite the significantly greater cytolytic responses in normal PBMC cultures than in SLE PBMC cultures, cytolytic responses in normal purified T cell cultures were only modestly and insignificantly greater than those in SLE purified T cell cultures. Moreover, substitution of 'healthy' non-T cells for SLE non-T cells in four of the nine MZ twin-pairs appreciably enhanced cytolytic responses, and substitution of SLE non-T cells for 'healthy' non-T cells in five of the seven twin-pairs tested appreciably diminished cytolytic responses. Taken together, these results indicate that, in addition to any inherent SLE T cell abnormalities, impaired function of SLE non-T cells contributes to impaired generation of nonrestricted CTL activity.

Antibodies, Monoclonal↗
PubMed1998

Superantigen-driven, CD8+ T cell-mediated down-regulation: CD95 (Fas)-dependent down-regulation of human Ig responses despite CD95-independent killing of activated B cells.

Staphylococcal superantigens, including staphylococcal enterotoxin B (SEB), promote vigorous T cell-dependent Ig responses at low dose (0.01 ng/ml). In contrast, more mitogenic high dose SEB (100 ng/ml) profoundly inhibits the Ig responses. To assess the contribution of CD8+ T cells to this inhibition, high dose SEB-dependent killing of activated B cells and down-regulation of Ig responses were determined. Rapid killing (4 h) of activated B cells was effected by high dose SEB-activated CD8+ T cells (CD8*), but not by high-dose SEB-activated CD4+ T cells (CD4*), and required the presence of high dose SEB during the cytotoxicity assay. This killing was abrogated by chelation of extracellular calcium or by treatment with concanamycin A but was only modestly affected by treatment with brefeldin A, suggesting a perforin-based pathway of killing. Despite their widely disparate abilities to rapidly kill activated B cells, CD8* and CD4* demonstrated similar quantitative abilities to effect high dose SEB-dependent down-regulation of Ig responses. Antagonist anti-CD95 mAb substantially reversed high dose SEB-dependent downregulation effected by CD8* but had no appreciable effects on high dose SEB-dependent killing of activated B cells. These observations strongly suggest that the small fraction of activated B cells that secrete Ig are selectively sensitive to CD95-based killing but resistant to CD95-independent killing. This finding may help explain why clinical autoimmunity associated with increased titers of autoantibodies is a predominant feature of defects in CD95 or CD95 ligand.

Anti-Bacterial Agents↗
PubMed1998

CD95 (Fas)-based, superantigen-dependent, CD4+ T cell-mediated down-regulation of human in vitro immunoglobulin responses.

Naturally occurring microbial superantigens (SAg) have been implicated in several human idiopathic disorders, and a compelling argument for the role of SAg in autoantibody-associated disorders, such as systemic lupus erythematosus, has been proposed. To test the effects of SAg on human in vitro Ig responses, CD4+ T cell + B cell cultures were stimulated with graded doses of staphylococcal enterotoxin B (SEB). Ig-secreting cell (IgSC) responses were very weak in CD4+ T cell + B cell cultures stimulated with SEB at the optimal mitogenic concentration (high dose SEB; 100 ng/ml) but were strong in parallel cultures stimulated with low dose SEB (0.01 ng/ml). High dose SEB actually enhanced B cell differentiation in the presence of CD4+ T cell soluble helper factors as long as the B cells were prevented from physically contacting the CD4+ T cells. However, when cell-cell contact between CD4+ T cells and B cells was permitted, high dose, but not low dose, SEB promoted increased CD4+ T cell-mediated B cell apoptosis with resulting decreases in viable CD20+ B cells and IgSC. High dose, but not low dose, SEB triggered increased levels of soluble CD95 ligand, and down-regulation of IgSC responses and incremental apoptosis of activated B cells were prevented by antagonist anti-CD95 mAb. This strongly suggests that CD4+ T cell-mediated CD95-based killing of activated B cells plays a major role in controlling SEB-driven IgSC responses. Defects in SAg-based down-regulation may contribute to autoimmune disorders such as SLE.

Antibodies, Monoclonal↗
PubMed1997

Impaired nonrestricted cytolytic activity in systemic lupus erythematosus: involvement of a pathway independent of Fas, tumor necrosis factor, and extracellular ATP that is associated with little detectable perforin.

OBJECTIVE: To determine the cytolytic effector pathway involved in impaired generation of nonrestricted cytolytic activity in systemic lupus erythematosus (SLE). METHODS: Peripheral blood mononuclear cells (PBMC) from normal subjects and SLE patients were stimulated in vitro with anti-CD3 monoclonal antibody (MAb) and interleukin-2 to promote the generation of nonrestricted cytolytic activity. On day 13 of culture, the PBMC were assayed for cytolytic activity against Fas-Daudi cells and Fas+ Jurkat cells. The effects on cytotoxicity of calcium chelation, antagonist anti-Fas MAb, tumor necrosis factor (TNF) alpha and beta, and ATP were measured. Intracellular perforin expression was determined by intracellular staining, and perforin messenger RNA levels were determined by quantitative competitive reverse transcription-polymerase chain reaction. RESULTS: We demonstrated the existence of a cytolytic pathway that is independent of Fas, TNF alpha, TNF beta, and ATP, but is dependent upon extracellular calcium. Despite its calcium dependence, this pathway is associated with low-to-undetectable levels of perforin. CONCLUSION: Impaired generation of nonrestricted cytolytic activity in SLE is likely due to decreased activity of this Fas-, TNF alpha-, TNF beta-, ATP-independent pathway associated with very low levels of perforin.

Adenosine Triphosphate↗
PubMed1996

Impaired recovery and cytolytic function of CD56+ T and non-T cells in systemic lupus erythematosus following in vitro polyclonal T cell stimulation. Studies in unselected patients and monozygotic disease-discordant twins.

OBJECTIVE: To determine whether there is impaired generation and cytolytic function of CD56+ T cells and non-T cells in human systemic lupus erythematosus (SLE). METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 73 patients with SLE, 39 normal controls, and 9 pairs of monozygotic (MZ) twins discordant for SLE. PBMC were stimulated with anti-CD3 monoclonal antibody, maintained in interleukin-2, and assayed for percentages of total CD56+ cells and CD56+ T cells by flow cytometry, and for cytolytic activity against 51Cr-labeled Daudi target cells. RESULTS: Despite normal total cell expansion, the percentages of recovered CD56+ T cells and total CD56+ cells were 1.6-fold and 1.8-fold lower, respectively, in patients with SLE compared with normal controls (P = 0.011 and P < 0.001, respectively). Cytolytic activities of isolated total CD56+ cells and CD56+ T cells and were also reduced in patients with SLE compared with normal controls (P = 0.033). These defects associated with SLE were independent of disease activity and immunosuppressive medications, and they reflected impaired maturation of cytolytic effector cells rather than a deficiency in precursor cell number. In MZ twins discordant for SLE, recovered percentages of CD56+ cells and cytolytic responses were very low in 4 of 8 and 6 of 9 co-twins with SLE, respectively. Cellmixing experiments with the PBMC of the MZ twins demonstrated that the E+ cell fractions (containing all T cells and CD56+ non-T cells) from the co-twins with SLE had decreased ability to generate cytolytic activity compared with the corresponding E+ cell fractions from the healthy co-twins. However, recovered percentages of CD56+ cells and non-T cells and cytolytic responses were also depressed in 4 of 8 and 4 of 9 healthy co-twins, respectively. CONCLUSION: Impaired CD56+ T cell and non-T cell responses are a feature of SLE and may antedate the onset of clinical disease.

Adult↗
PubMed1996

In vitro inhibition by intravenous immunoglobulin of human T cell-dependent B cell differentiation induced by staphylococcal superantigens.

Treatment with intravenous Ig (IVIG) is efficacious not only in humoral immunodeficiency diseases but in several nonimmunodeficiency disorders as well. Since microbial superantigens (SAg) have been postulated to play a role in promoting in vivo pathogenic autoantibody production and since IVIG preparations are rich in anti-SAg antibodies, we tested whether IVIG could inhibit in vitro SAg-driven human T cell-dependent B cell differentiation. We demonstrate that IVIG inhibits such B cell differentiation by at least three different mechanisms. Early addition of IVIG inhibits B cell differentiation not only in SAg-stimulated PBMC cultures but in anti-CD3- and pokeweed mitogen (PWM)-stimulated cultures as well, pointing to a SAg-nonspecific inhibitory effect. However, anti-SAg antibodies contained in IVIG can also effect SAg-specific inhibition, since polyclonal rabbit anti-SAg antisera added early to peripheral blood mononuclear cell (PBMC) cultures inhibit neither anti-CD3- nor PWM-driven B cell differentiation and inhibit B cell differentiation triggered only by the specific SAg against which the individual antiserum was raised. Finally, late addition of IVIG at a time at which B cells have already committed to terminal differentiation inhibits SAg-driven, but not anti-CD3- or PWM-driven, generation of Ig-secreting cells (IgSC). This late inhibition is associated with enhanced SAg-dependent cytolytic activity against Raji cell targets which is dramatic in PBMC cultures but is often not detectable in T + B cell cultures. Reconstitution of T + B cell cultures with natural killer cells restores the enhancing capacity of IVIG on SAg-dependent cytolytic activity as well as the late inhibitory effects of IVIG on IgSC generation. Understanding the multiple mechanisms through which IVIG can inhibit SAg-driven B cell differentiation may offer a rational basis for determining which patients are likely to favorably respond to IVIG administration.

Antibodies, Monoclonal↗
PubMed1995

Differential human T cell-dependent B cell differentiation induced by staphylococcal superantigens (SAg). Regulatory role for SAg-dependent B cell cytolysis.

Microbial superantigens (SAg), by virtue of their binding to TCR V beta elements and to class II MHC molecules on accessory cells, trigger T cell proliferation in a dose-dependent fashion. In contrast, SAg-induced T cell-dependent B cell differentiation occurs only at SAg concentrations that are orders of magnitude lower that those required for optimal mitogenesis (low-dose SAg). At optimal mitogenic doses (high-dose SAg), SAg-driven B cell differentiation does not ensue. In this report, we demonstrate that this dichotomy in SAg-driven B cell differentiation is due to the active inhibition of B cell differentiation by high-dose SAg. Such inhibition is not reversed by feeding cultures with fresh medium, with conditioned media, or with IL2 +/- IL4, and impaired B cell differentiation is observed in cultures containing purified T cells or CD4+ T cells + B cells, as well as in PBMC cultures. Although preincubation of either T cells or B cells with high-dose SAg impairs subsequent SAg-induced B cell differentiation, high-dose SAg is not toxic per se, since high-dose SAg does promote vigorous B cell differentiation in cultures of mitomycin C-treated T cells + B cells and does not inhibit T cell-independent B cell differentiation. No correlation exists between SAg-induced B cell surface expression of CTLA4 ligand and generation of Ig-secreting cells, but the dose of SAg does correlate with T cell-mediated SAg-dependent cytolysis of transformed B cell targets or autologous nontransformed activated B cell targets. B cell recovery from cultures stimulated with high-dose SAg is lower than that from cultures stimulated with low-dose SAg, whereas B cell apoptosis is greater in the former cultures than that in the latter cultures. T cells stimulated with high-dose SAg do not inhibit differentiation of activated B cells in the absence of physical contact between the T cells and the target B cells, supporting the notion of direct killing of activated B cells by T cells. The ability of low doses of SAg to promote B cell differentiation without generating biologically meaningful cytolytic activity and the ability of higher doses of SAg to modulate Ig production may have important pathogenetic and therapeutic ramifications for certain autoimmune disorders, such as systemic lupus erythematosus.

B-Lymphocytes↗
PubMed1995

Impaired polyclonal T cell cytolytic activity. A possible risk factor for systemic lupus erythematosus.

OBJECTIVE: To determine whether impaired generation of polyclonal T cell cytolytic activity is over-represented in systemic lupus erythematosus (SLE) compared with other rheumatologic diseases and whether such impaired generation of cytolytic activity waxes and wanes with disease activity and/or changes in medications. METHODS: Peripheral blood mononuclear cells from 84 SLE patients, 55 rheumatologic disease (RD) controls, and 44 normal subjects were stimulated with anti-CD3 monoclonal antibody, maintained in interleukin-2, and assayed for cytolytic activity against 51Cr-labeled Daudi target cells. RESULTS: Generation of cytolytic activity was significantly lower in SLE patients than in either RD or normal controls. Abnormal cytolytic responses in SLE could not be attributed to the patient's sex, race, age, disease activity, or antirheumatic medications (including corticosteroids and cytotoxics), although both SLE and RD patients taking azathioprine (AZA) manifested lower responses than did corresponding patients not taking AZA. Abnormal cytolytic activity reflected, in large measure, impaired cytolytic activity of CD8+ T cells. No significant difference in the generation of cytolytic activity between RD and normal controls was detected. CONCLUSION: Impaired generation of polyclonal T cell cytolytic activity may be a predisposing factor in the development of SLE.

Antirheumatic Agents↗
PubMed1994

Human T cell-dependent B cell differentiation induced by staphylococcal superantigens.

Microbial superantigens (SAgs), by virtue of their binding to TCR V beta elements on T cells and to class II MHC molecules on accessory cells (AC), trigger T cell activation. Although anti-CD3 mAb (which also trigger T cell activation via surface CD3/TCR) can readily induce T cell-dependent B cell differentiation in unmanipulated PBMC cultures, induction of Ig production in SAg-stimulated cultures has usually required special manipulation of the T cells, such as irradiating them or treating them with mitomycin C. We now demonstrate that eight different staphylococcal SAgs, typically at concentrations 10- to 100-fold lower than those required for proliferation, can each trigger unmanipulated peripheral blood and tonsil T cells to drive polyclonal B cell differentiation. Such SAg-induced T cell-dependent generation of Ig-secreting cells (IgSC) requires T cells and B cells only and occurs in the absence of monocytes as long as there are adequate numbers of B cells to serve as (DR+) AC. Physical contact among T cells, responder B cells, and AC (when different from the responder B cells) is required. The fusion protein CTLA4Ig inhibits SAg-induced IgSC generation in a dose-dependent fashion, whereas a control fusion protein has no such effect. In contrast, CTLA4Ig has, at best, only modest effects on SAg-induced T cell proliferation, indicating that CD28 (CTLA4)/B7 (B7-like) interactions play a more prominent role in SAg-induced IgSC generation than in SAg-induced T cell proliferation. These results establish SAg-induced T cell-dependent B cell differentiation as a useful model for T cell/B cell interactions, inasmuch as no other cell types are necessary for successful B cell differentiation; these results also demonstrate the importance of CD28 (CTLA4)/B7 (B7-like)-dependent mechanisms in this process.

Abatacept↗