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Loss of intra-islet CD20 expression may complicate efficacy of B-cell-directed type 1 diabetes therapies.

Serreze DV, Chapman HD, Niens M, Dunn R, Kehry MR, Driver JP, Haller M, Wasserfall C, Atkinson MA - Diabetes (2011)

Bottom Line: One implication of these results is that the FO subset of B cells preferentially contributes to early diabetes initiation events.However, most important, the inefficient ability of anti-CD20 treatment to exert late-stage diabetes prevention was found to be attributable to downregulation of CD20 expression upon B cell entry into pancreatic islets.These findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA. dave.serreze@jax.org

ABSTRACT

Objective: Consistent with studies in NOD mice, early clinical trials addressing whether depletion of B cells by the Rituximab CD20-specific antibody provides an effective means for type 1 diabetes reversal have produced promising results. However, to improve therapeutic efficacy, additional B-cell-depleting agents, as well as attempts seeking diabetes prevention, are being considered.

Research design and methods: Autoantibodies, including those against insulin (IAAs), are used to identify at-risk subjects for inclusion in diabetes prevention trials. Therefore, we tested the ability of anti-CD20 to prevent diabetes in NOD mice when administered either before or after IAA onset.

Results: The murine CD20-specific 18B12 antibody that like Rituximab, depletes the follicular (FO) but not marginal zone subset of B cells, efficiently inhibited diabetes development in NOD mice in a likely regulatory T-cell-dependent manner only when treatment was initiated before IAA detection. One implication of these results is that the FO subset of B cells preferentially contributes to early diabetes initiation events. However, most important, the inefficient ability of anti-CD20 treatment to exert late-stage diabetes prevention was found to be attributable to downregulation of CD20 expression upon B cell entry into pancreatic islets.

Conclusions: These findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.

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Related in: MedlinePlus

Both Tregs and diabetogenic BDC2.5 clonotypic CD4 T cells expand within PLNs of NOD mice depleted of FO B cells by anti-CD20 treatment. Beginning at 4 weeks of age, NOD females received two injections at a 21-day interval of the CD20-specific or control antibody and at 4–7 days after the second treatment, were assessed for numbers of (A) total CD4 T cells, (B) BDC2.5 clonotypic cells by specific tetramer staining, and (C) Tregs within PLNs. Noted statistical significance values were determined by ANOVA analyses. Aby, antibody.
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Figure 5: Both Tregs and diabetogenic BDC2.5 clonotypic CD4 T cells expand within PLNs of NOD mice depleted of FO B cells by anti-CD20 treatment. Beginning at 4 weeks of age, NOD females received two injections at a 21-day interval of the CD20-specific or control antibody and at 4–7 days after the second treatment, were assessed for numbers of (A) total CD4 T cells, (B) BDC2.5 clonotypic cells by specific tetramer staining, and (C) Tregs within PLNs. Noted statistical significance values were determined by ANOVA analyses. Aby, antibody.

Mentions: Compared with controls, total CD4 T cells were significantly increased in the PLNs of NOD mice selectively depleted of FO B cells by anti-CD20 treatment (Fig. 5A). There was an even greater significant increase of total CD4 T cells within PLNs of totally B-cell–deficient NOD.Igµ mice (Fig. 5A). In contrast, numbers of BDC2.5-like diabetogenic CD4 T cells detected by tetramer staining did not differ in PLNs from NOD control or NOD.Igµ mice (Fig. 5B). Compared with controls, numbers of BDC2.5-like CD4 T cells were somewhat higher in PLNs of anti-CD20–treated NOD mice, but this difference achieved only marginal statistical significance (Fig. 5B). However, the ability to inhibit diabetes development in NOD mice by genetically ablating all B cells or selectively eliminating the FO subset was also associated with significantly increased numbers of phenotypic Tregs (CD4+ CD25+ FoxP3+) within PLNs (Fig. 5C). Splenic Treg numbers were not increased in either anti-CD20–treated NOD mice or the NOD.Igµ stock (data not shown). Thus, the intra-PLN expansion of Tregs in anti-CD20–treated NOD mice and the NOD.Igµ stock is most likely an antigen-dependent process.


Loss of intra-islet CD20 expression may complicate efficacy of B-cell-directed type 1 diabetes therapies.

Serreze DV, Chapman HD, Niens M, Dunn R, Kehry MR, Driver JP, Haller M, Wasserfall C, Atkinson MA - Diabetes (2011)

Both Tregs and diabetogenic BDC2.5 clonotypic CD4 T cells expand within PLNs of NOD mice depleted of FO B cells by anti-CD20 treatment. Beginning at 4 weeks of age, NOD females received two injections at a 21-day interval of the CD20-specific or control antibody and at 4–7 days after the second treatment, were assessed for numbers of (A) total CD4 T cells, (B) BDC2.5 clonotypic cells by specific tetramer staining, and (C) Tregs within PLNs. Noted statistical significance values were determined by ANOVA analyses. Aby, antibody.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198088&req=5

Figure 5: Both Tregs and diabetogenic BDC2.5 clonotypic CD4 T cells expand within PLNs of NOD mice depleted of FO B cells by anti-CD20 treatment. Beginning at 4 weeks of age, NOD females received two injections at a 21-day interval of the CD20-specific or control antibody and at 4–7 days after the second treatment, were assessed for numbers of (A) total CD4 T cells, (B) BDC2.5 clonotypic cells by specific tetramer staining, and (C) Tregs within PLNs. Noted statistical significance values were determined by ANOVA analyses. Aby, antibody.
Mentions: Compared with controls, total CD4 T cells were significantly increased in the PLNs of NOD mice selectively depleted of FO B cells by anti-CD20 treatment (Fig. 5A). There was an even greater significant increase of total CD4 T cells within PLNs of totally B-cell–deficient NOD.Igµ mice (Fig. 5A). In contrast, numbers of BDC2.5-like diabetogenic CD4 T cells detected by tetramer staining did not differ in PLNs from NOD control or NOD.Igµ mice (Fig. 5B). Compared with controls, numbers of BDC2.5-like CD4 T cells were somewhat higher in PLNs of anti-CD20–treated NOD mice, but this difference achieved only marginal statistical significance (Fig. 5B). However, the ability to inhibit diabetes development in NOD mice by genetically ablating all B cells or selectively eliminating the FO subset was also associated with significantly increased numbers of phenotypic Tregs (CD4+ CD25+ FoxP3+) within PLNs (Fig. 5C). Splenic Treg numbers were not increased in either anti-CD20–treated NOD mice or the NOD.Igµ stock (data not shown). Thus, the intra-PLN expansion of Tregs in anti-CD20–treated NOD mice and the NOD.Igµ stock is most likely an antigen-dependent process.

Bottom Line: One implication of these results is that the FO subset of B cells preferentially contributes to early diabetes initiation events.However, most important, the inefficient ability of anti-CD20 treatment to exert late-stage diabetes prevention was found to be attributable to downregulation of CD20 expression upon B cell entry into pancreatic islets.These findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.

View Article: PubMed Central - PubMed

Affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA. dave.serreze@jax.org

ABSTRACT

Objective: Consistent with studies in NOD mice, early clinical trials addressing whether depletion of B cells by the Rituximab CD20-specific antibody provides an effective means for type 1 diabetes reversal have produced promising results. However, to improve therapeutic efficacy, additional B-cell-depleting agents, as well as attempts seeking diabetes prevention, are being considered.

Research design and methods: Autoantibodies, including those against insulin (IAAs), are used to identify at-risk subjects for inclusion in diabetes prevention trials. Therefore, we tested the ability of anti-CD20 to prevent diabetes in NOD mice when administered either before or after IAA onset.

Results: The murine CD20-specific 18B12 antibody that like Rituximab, depletes the follicular (FO) but not marginal zone subset of B cells, efficiently inhibited diabetes development in NOD mice in a likely regulatory T-cell-dependent manner only when treatment was initiated before IAA detection. One implication of these results is that the FO subset of B cells preferentially contributes to early diabetes initiation events. However, most important, the inefficient ability of anti-CD20 treatment to exert late-stage diabetes prevention was found to be attributable to downregulation of CD20 expression upon B cell entry into pancreatic islets.

Conclusions: These findings provide important guidance for designing strategies targeting B cells as a potential means of diabetes intervention.

Show MeSH
Related in: MedlinePlus