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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

Peripheral blood B cells in NOD mice are efficiently deleted by the IgG1 isotype of the 18B12 murine CD20-specific antibody. NOD female mice were initially injected intraperitoneally at 8 weeks of age with 10 mg/kg body wt of the IgG1 anti-CD20 isotype, with controls treated with a similar dose of the irrelevant 2B8 antibody (n = 3 per group). Proportions of B cells among peripheral blood leukocytes were then monitored over time. Depletion of peripheral blood B cells was safely maintained by repeated injection of the IgG1 18B12 antibody at 21-day intervals. PBL, peripheral blood.
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Figure 1: Peripheral blood B cells in NOD mice are efficiently deleted by the IgG1 isotype of the 18B12 murine CD20-specific antibody. NOD female mice were initially injected intraperitoneally at 8 weeks of age with 10 mg/kg body wt of the IgG1 anti-CD20 isotype, with controls treated with a similar dose of the irrelevant 2B8 antibody (n = 3 per group). Proportions of B cells among peripheral blood leukocytes were then monitored over time. Depletion of peripheral blood B cells was safely maintained by repeated injection of the IgG1 18B12 antibody at 21-day intervals. PBL, peripheral blood.

Mentions: The IgG1 isotype of the 18B12 murine CD20-specific antibody rapidly depleted peripheral blood B cells in NOD mice, with minimal rebounding observed at day 21 posttreatment (Fig. 1). NOD mice could be maintained in a state where peripheral blood B cells remained virtually absent by continuous treatments with the IgG1 anti-CD20 reagent at 21-day intervals (Fig. 1). NOD mice receiving a second treatment at 14 days after the first with the IgG2a isotype of 18B12 all succumbed to an anaphylaxis response within 24 h. Hence, the IgG1 anti-murine CD20 reagent was used for all subsequent experiments.


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)

Peripheral blood B cells in NOD mice are efficiently deleted by the IgG1 isotype of the 18B12 murine CD20-specific antibody. NOD female mice were initially injected intraperitoneally at 8 weeks of age with 10 mg/kg body wt of the IgG1 anti-CD20 isotype, with controls treated with a similar dose of the irrelevant 2B8 antibody (n = 3 per group). Proportions of B cells among peripheral blood leukocytes were then monitored over time. Depletion of peripheral blood B cells was safely maintained by repeated injection of the IgG1 18B12 antibody at 21-day intervals. PBL, peripheral blood.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 1: Peripheral blood B cells in NOD mice are efficiently deleted by the IgG1 isotype of the 18B12 murine CD20-specific antibody. NOD female mice were initially injected intraperitoneally at 8 weeks of age with 10 mg/kg body wt of the IgG1 anti-CD20 isotype, with controls treated with a similar dose of the irrelevant 2B8 antibody (n = 3 per group). Proportions of B cells among peripheral blood leukocytes were then monitored over time. Depletion of peripheral blood B cells was safely maintained by repeated injection of the IgG1 18B12 antibody at 21-day intervals. PBL, peripheral blood.
Mentions: The IgG1 isotype of the 18B12 murine CD20-specific antibody rapidly depleted peripheral blood B cells in NOD mice, with minimal rebounding observed at day 21 posttreatment (Fig. 1). NOD mice could be maintained in a state where peripheral blood B cells remained virtually absent by continuous treatments with the IgG1 anti-CD20 reagent at 21-day intervals (Fig. 1). NOD mice receiving a second treatment at 14 days after the first with the IgG2a isotype of 18B12 all succumbed to an anaphylaxis response within 24 h. Hence, the IgG1 anti-murine CD20 reagent was used for all subsequent experiments.

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