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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

Coablation of Tregs abrogates the diabetes protective effects of selectively eliminating FO B cells in pre-IAA onset NOD mice. Anti-CD20 or control antibody treatment was initiated in 10-week-old NOD female mice typed to be IAA negative, with a subset also injected at 2-week intervals with a CD25-specific antibody to deplete Tregs. Compared with controls, diabetes development was significantly decreased only in NOD mice treated with anti-CD20 alone (P = 0.0175, Kaplan-Meier analyses). T1D, type 1 diabetes.
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Figure 6: Coablation of Tregs abrogates the diabetes protective effects of selectively eliminating FO B cells in pre-IAA onset NOD mice. Anti-CD20 or control antibody treatment was initiated in 10-week-old NOD female mice typed to be IAA negative, with a subset also injected at 2-week intervals with a CD25-specific antibody to deplete Tregs. Compared with controls, diabetes development was significantly decreased only in NOD mice treated with anti-CD20 alone (P = 0.0175, Kaplan-Meier analyses). T1D, type 1 diabetes.

Mentions: While numerically increased, on a per cell basis, Treg functional activity in anti-CD20–treated NOD mice was equivalent to that in controls (Supplementary Fig. 4). We then tested if the elicited numerical increase in Tregs might contribute to the ability of anti-CD20 treatment to inhibit diabetes development when initiated in pre-IAA onset NOD mice. As expected, compared with controls, diabetes development was significantly reduced in NOD mice in which anti-CD20 treatment was initiated before IAA onset (Fig. 6). Unlike other T-cell types, Tregs constitutively express CD25 (40). It is significant that the ability of anti-CD20 treatment to inhibit diabetes development in pre-IAA onset NOD mice was abrogated by coinfusions with a depleting CD25-specific antibody to a disease rate indistinguishable from controls (Fig. 6). Hence, anti-CD25 coinfusions did not abrogate the diabetes protective effects of anti-CD20 treatment by eliciting alterations in pathogenic effector T-cell activity differing from in NOD control mice. Further supporting this conclusion is the finding that while Tregs were reduced, there was no loss in conventional CD4 and CD8 T cells in coanti-CD20/CD25–treated NOD mice (Supplementary Fig. 5). Instead, these results support a possible Treg-dependent component for the mechanism by which selective depletion of FO subset B cells inhibits diabetes development in pre-IAA onset 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)

Coablation of Tregs abrogates the diabetes protective effects of selectively eliminating FO B cells in pre-IAA onset NOD mice. Anti-CD20 or control antibody treatment was initiated in 10-week-old NOD female mice typed to be IAA negative, with a subset also injected at 2-week intervals with a CD25-specific antibody to deplete Tregs. Compared with controls, diabetes development was significantly decreased only in NOD mice treated with anti-CD20 alone (P = 0.0175, Kaplan-Meier analyses). T1D, type 1 diabetes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 6: Coablation of Tregs abrogates the diabetes protective effects of selectively eliminating FO B cells in pre-IAA onset NOD mice. Anti-CD20 or control antibody treatment was initiated in 10-week-old NOD female mice typed to be IAA negative, with a subset also injected at 2-week intervals with a CD25-specific antibody to deplete Tregs. Compared with controls, diabetes development was significantly decreased only in NOD mice treated with anti-CD20 alone (P = 0.0175, Kaplan-Meier analyses). T1D, type 1 diabetes.
Mentions: While numerically increased, on a per cell basis, Treg functional activity in anti-CD20–treated NOD mice was equivalent to that in controls (Supplementary Fig. 4). We then tested if the elicited numerical increase in Tregs might contribute to the ability of anti-CD20 treatment to inhibit diabetes development when initiated in pre-IAA onset NOD mice. As expected, compared with controls, diabetes development was significantly reduced in NOD mice in which anti-CD20 treatment was initiated before IAA onset (Fig. 6). Unlike other T-cell types, Tregs constitutively express CD25 (40). It is significant that the ability of anti-CD20 treatment to inhibit diabetes development in pre-IAA onset NOD mice was abrogated by coinfusions with a depleting CD25-specific antibody to a disease rate indistinguishable from controls (Fig. 6). Hence, anti-CD25 coinfusions did not abrogate the diabetes protective effects of anti-CD20 treatment by eliciting alterations in pathogenic effector T-cell activity differing from in NOD control mice. Further supporting this conclusion is the finding that while Tregs were reduced, there was no loss in conventional CD4 and CD8 T cells in coanti-CD20/CD25–treated NOD mice (Supplementary Fig. 5). Instead, these results support a possible Treg-dependent component for the mechanism by which selective depletion of FO subset B cells inhibits diabetes development in pre-IAA onset 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