Multiple Pathways of B Lymphocyte Tolerance

Scott, David W.; Venkataraman, Maanasa; Jandinski, John J.

doi:10.1111/j.1600-065x.1979.tb00424.x

Cited by 69 publications

(35 citation statements)

References 61 publications

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“…Experiments designed to test such hypotheses have been reviewed (27)(28)(29). Sidman and Unanue (30) and Sieckmann et al (31) have shown by cell sorting experiments that the subset of B cells which responds to anti-pt antibodies by DNA synthesis has relatively large amounts of sIgD.…”

Section: Discussionmentioning

confidence: 99%

Activation of murine B lymphocytes by anti-immunoglobulin is an inductive signal leading to immunoglobulin secretion.

Parker¹,

Wadsworth²,

Schneider³

1980

The Journal of Experimental Medicine

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Cultures of isolated mouse splenic B lymphocytes activated by the divalent F(ab')2 fragment of purified rabbit anti-mouse Fab or class-specific anti-mouse IgM antibodies can be driven on to high rate Ig secretion by the addition of the supernatant fluid of a 24-h culture of concanavalin A-activated spleen cells (SN). The polyclonal antibody response to anti-Ig pus SN is comparable in magnitude with the lipopolysaccharide response as measured in a reverse plaque assay. The addition of SN can be delayed for 24 h after addition of anti-Ig without changing the kinetics of the response. Addition at 48 h delays the response by 24 h. The response to F(ab')2 anti-Fab plus SN is sensitive to Fc-dependent inhibition because intact anti-Fab antibodies inhibit strongly at relatively low concentrations. The monovalent Fab' fragment fails to induce Ig secretion, indicating that cross-linkage of surface immunoglobulin is required. Although the production of active SN is T cell dependent, the response to anti-Ig plus SN is T independent. These findings are interpreted as a polyclonal model of a thymus-dependent antibody response. X

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of murine B lymphocytes by anti-immunoglobulin is an inductive signal leading to immunoglobulin secretion.

Parker¹,

Wadsworth²,

Schneider³

1980

The Journal of Experimental Medicine

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show abstract

“…Because one of the most tolerogenic APCs is the B cell, and one of the most tolerogenic carriers is IgG (11)(12)(13)(14), our laboratory has developed protocols to gene transfer IgG-fusion proteins into B lymphocytes that are then used to express self IgG-fusion protein in vivo. Previously, we found that in primed mice, the expression of a model Ag in B cells as part of an IgG scaffold down-regulated both the Th1 and Th2 arms of the immunologic response (3,6).…”

Section: Discussionmentioning

confidence: 99%

Gene Transfer of Ig-Fusion Proteins Into B Cells Prevents and Treats Autoimmune Diseases

Melo

Qian

El-Amine

et al. 2002

The Journal of Immunology

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106

110

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Based on the tolerogenic properties of IgG carriers and B cell Ag presentation, we developed a retrovirally mediated gene expression approach for treatment of autoimmune conditions. In this study, we show that the IgG-Ag retroviral constructs, expressing myelin basic protein (MBP) or glutamic acid decarboxylase in B cells, can be used for the treatment of murine models for multiple sclerosis and diabetes. Transduction of syngeneic B cells with MBP-IgG leads to the amelioration of ongoing experimental allergic encephalomyelitis induced by the transfer of primed cells from PL×SJL F1 mice with ongoing disease and could be effective even after symptoms appeared. This effect is specific and does not involve bystander suppression because treatment with MBP-IgG does not affect disease induced after immunization with proteolipid protein immunodominant peptide plus MBP. Interestingly, if donor B cells are derived from gld mice (Fas ligand-negative), then tolerance is not induced with a model Ag although there was no evidence for Fas ligand-mediated deletion of target T cells. In spontaneous diabetes in nonobese diabetic mice, we were able to stop the ongoing autoimmune process by treatment at 7–10 wk with glutamic acid decarboxylase-IgG retrovirally transduced B cells, or attenuate it with B cells transduced with an insulin B chain (B9–23) epitope IgG fusion protein. Furthermore, IgG fusion protein gene therapy can also protect primed recipients from Ag-induced anaphylactic shock, and thus does not cause immune deviation. These results demonstrate proof of principle for future efforts to develop this approach in a clinical setting.

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“…O ur laboratory has shown that IgG fusion proteins, delivered via retroviral gene therapy for B cell Ag presentation, are highly tolerogenic for the epitopes associated with the IgG (1)(2)(3)(4). In this system, retroviral constructs have been engineered with an immunodominant epitope (e.g., p12-26 of the cI repressor molecule) or full-length protein (e.g., OVA) in frame at the N terminus of a murine IgG1 H chain (4).…”

mentioning

confidence: 99%

Mechanisms of Gene Therapy for Tolerance: B7 Signaling Is Required for Peptide-IgG Gene-Transferred Tolerance Induction

Litzinger

Lei

et al. 2005

The Journal of Immunology

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LPS-activated B cells, transduced with IgG fusion proteins, are highly tolerogenic APCs. To analyze the mechanisms for this B cell-delivered gene therapy, we first followed the fate of CFSE-labeled B cell blasts. These cells primarily localized to the spleen, where a small population persisted for at least 1 mo after injection. By day 7 after injection, ∼95% of the transduced cells had divided at least once, presumably an effect of the in vitro LPS activation into the cycle, because resting cells did not divide. B cells from gld donors were not tolerogenic, initially suggesting a role for Fas ligand (FasL) in tolerance. Because transduced normal B cells expressed only low levels of FasL and did not kill Fas-expressing Jurkat or A20 B lymphoma cells in vitro, these data suggest that gld B cells are not tolerogenic due to unique characteristics of these B cells rather than the lack of functional FasL expression. The transduced B cell blasts displayed significant up-regulation of both B7 costimulatory molecules, and B7.2 up-regulation was maintained through day 7 in vivo. When B cells from B7 knockout donors were transduced to express Ig fusion proteins, they were not tolerogenic in two different mouse strains and Ag models. Moreover, anti-B7 Ab blocked tolerance induction in this model, a result consistent with a role for B7 in tolerance induction. We propose that tolerance may be induced in this model by B7-driven negative regulatory signaling, but tolerance is maintained by a lack of signal 2, because expression of B7 is eventually lost in vivo.

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Multiple Pathways of B Lymphocyte Tolerance

Cited by 69 publications

References 61 publications

Activation of murine B lymphocytes by anti-immunoglobulin is an inductive signal leading to immunoglobulin secretion.

Activation of murine B lymphocytes by anti-immunoglobulin is an inductive signal leading to immunoglobulin secretion.

Gene Transfer of Ig-Fusion Proteins Into B Cells Prevents and Treats Autoimmune Diseases

Mechanisms of Gene Therapy for Tolerance: B7 Signaling Is Required for Peptide-IgG Gene-Transferred Tolerance Induction

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