Limits...
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.

Show MeSH

Related in: MedlinePlus

Anti-CD20–mediated B-cell depletion strongly inhibits progression to overt diabetes development only when initiated in NOD mice that have not yet become IAA positive. A: Serum was collected from 10-week-old NOD female mice that then immediately began to receive treatments at 21-day intervals with the IgG1 CD20-specific or control antibody at a 10 mg/kg body wt dose. Serum samples were retrospectively assessed for the presence of IAAs and the mice monitored for diabetes development. Mice used for the analyses had a spread of eight separate birth dates and, thus, were entered into the treatment groups in a staggered fashion. Anti-CD20 treatment significantly suppressed diabetes development in the IAA-negative (P = 0.04) but not IAA-positive recipients (P = 0.14, Kaplan-Meier analyses). B: IAA-negative NOD female mice receiving a single anti-CD20 treatment at 10 weeks of age were not protected from subsequent diabetes development. Aby, antibody.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3198088&req=5

Figure 2: Anti-CD20–mediated B-cell depletion strongly inhibits progression to overt diabetes development only when initiated in NOD mice that have not yet become IAA positive. A: Serum was collected from 10-week-old NOD female mice that then immediately began to receive treatments at 21-day intervals with the IgG1 CD20-specific or control antibody at a 10 mg/kg body wt dose. Serum samples were retrospectively assessed for the presence of IAAs and the mice monitored for diabetes development. Mice used for the analyses had a spread of eight separate birth dates and, thus, were entered into the treatment groups in a staggered fashion. Anti-CD20 treatment significantly suppressed diabetes development in the IAA-negative (P = 0.04) but not IAA-positive recipients (P = 0.14, Kaplan-Meier analyses). B: IAA-negative NOD female mice receiving a single anti-CD20 treatment at 10 weeks of age were not protected from subsequent diabetes development. Aby, antibody.

Mentions: As expected, when initiated in pre-IAA onset NOD mice, anti-CD20 treatment significantly inhibited diabetes development (Fig. 2A). Among NOD mice treated with the irrelevant control antibody, the presence of IAAs marked a significantly increased propensity for progression to overt diabetes (100 vs. 64%) (Fig. 2A). Conversely, while anti-CD20 treatment may have a marginal capacity to inhibit diabetes development when initiated in already IAA-positive NOD mice, this effect did not achieve statistical significance (Fig. 2A). We cannot exclude the possibility that the minority subset of NOD mice typed as IAA negative at 10 weeks of age, and subsequently not protected from diabetes development by anti-CD20 treatment, was transiently positive at an earlier time point. However, overall, these results indicate B cells targetable by the 18B12 CD20-specific antibody appear to more prominently contribute to earlier rather than later stages of autoimmune diabetes development in NOD mice.


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)

Anti-CD20–mediated B-cell depletion strongly inhibits progression to overt diabetes development only when initiated in NOD mice that have not yet become IAA positive. A: Serum was collected from 10-week-old NOD female mice that then immediately began to receive treatments at 21-day intervals with the IgG1 CD20-specific or control antibody at a 10 mg/kg body wt dose. Serum samples were retrospectively assessed for the presence of IAAs and the mice monitored for diabetes development. Mice used for the analyses had a spread of eight separate birth dates and, thus, were entered into the treatment groups in a staggered fashion. Anti-CD20 treatment significantly suppressed diabetes development in the IAA-negative (P = 0.04) but not IAA-positive recipients (P = 0.14, Kaplan-Meier analyses). B: IAA-negative NOD female mice receiving a single anti-CD20 treatment at 10 weeks of age were not protected from subsequent diabetes development. Aby, antibody.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 2: Anti-CD20–mediated B-cell depletion strongly inhibits progression to overt diabetes development only when initiated in NOD mice that have not yet become IAA positive. A: Serum was collected from 10-week-old NOD female mice that then immediately began to receive treatments at 21-day intervals with the IgG1 CD20-specific or control antibody at a 10 mg/kg body wt dose. Serum samples were retrospectively assessed for the presence of IAAs and the mice monitored for diabetes development. Mice used for the analyses had a spread of eight separate birth dates and, thus, were entered into the treatment groups in a staggered fashion. Anti-CD20 treatment significantly suppressed diabetes development in the IAA-negative (P = 0.04) but not IAA-positive recipients (P = 0.14, Kaplan-Meier analyses). B: IAA-negative NOD female mice receiving a single anti-CD20 treatment at 10 weeks of age were not protected from subsequent diabetes development. Aby, antibody.
Mentions: As expected, when initiated in pre-IAA onset NOD mice, anti-CD20 treatment significantly inhibited diabetes development (Fig. 2A). Among NOD mice treated with the irrelevant control antibody, the presence of IAAs marked a significantly increased propensity for progression to overt diabetes (100 vs. 64%) (Fig. 2A). Conversely, while anti-CD20 treatment may have a marginal capacity to inhibit diabetes development when initiated in already IAA-positive NOD mice, this effect did not achieve statistical significance (Fig. 2A). We cannot exclude the possibility that the minority subset of NOD mice typed as IAA negative at 10 weeks of age, and subsequently not protected from diabetes development by anti-CD20 treatment, was transiently positive at an earlier time point. However, overall, these results indicate B cells targetable by the 18B12 CD20-specific antibody appear to more prominently contribute to earlier rather than later stages of autoimmune diabetes development in NOD mice.

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