B-Lymphocyte Depletion With Rituximab and β-Cell Function: Two-Year Results

Pescovitz, Mark D.; Greenbaum, Carla J.; Bundy, Brian N.; Becker, Dorothy J.; Gitelman, Stephen E.; Goland, Robin; Gottlieb, Peter A.; Marks, Jennifer B.; Moran, Antoinette; Raskin, Philip; Rodriguez, Henry; Schatz, Desmond; Wherrett, Diane K.; Wilson, Darrell M.; Krischer, Jeffrey P.; Skyler, Jay S.

doi:10.2337/dc13-0626

Cited by 223 publications

(195 citation statements)

References 17 publications

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“…Subjects received four weekly injections of rituximab and were then monitored for 12 months (Pescovitz et al 2009(Pescovitz et al , 2014. Adverse events of limited severity are mostly seen after the first infusion of Ab, and no increase in infections is detected in rituximab-treated subjects likely reflecting preservation of memory B cells.…”

Section: B Cell Depletionmentioning

confidence: 99%

Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes

Morillon

Martin

Gojanovich

et al. 2015

Arch. Immunol. Ther. Exp.

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Type 1 diabetes (T1D) is an autoimmune disease in which the insulin-producing b cells are selectively destroyed. b cell-specific T cells are considered to be the major mediators of pathology. Accordingly, most immunotherapies tested in the clinic to date have focused on reestablishing self-tolerance within the T cell compartment. Monoclonal antibodies (Ab) targeting a variety of lymphocyte surface proteins have demonstrated benefits in preclinical and clinical settings. Indeed, the use of Ab to target T cells directly or indirectly has proven to be an effective strategy to rapidly suppress b cell autoimmunity and establish tissue-specific, long-term tolerance in rodent T1D models. In this review, we describe a number of these Ab-based immunotherapies, discuss associated immune regulatory mechanisms, and highlight results obtained in T1D clinical trials.

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Section: B Cell Depletionmentioning

confidence: 99%

Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes

Morillon

Martin

Gojanovich

et al. 2015

Arch. Immunol. Ther. Exp.

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“…Antibodies for CD24(30-F1), CD4(GK1.5), IgM(II/41) IgD (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26), BP1(6C3), CD19(eBio1D3), CD43(eBioR2/60), and CD23(B3B4) as well as efluor 450-labeled streptavidin were purchased from eBioscience (San Diego, CA). Dead cells were excluded using DAPI or aqua fluorescent reactive dye (Invitrogen, Carlsbad, CA).…”

Section: Flow Cytometry and Antibodiesmentioning

confidence: 99%

“…These studies indicate that B cells play an important role in early priming and expansion of autoimmune responses. However, therapies that target B cells, including blockade of B-cell receptor (BCR) signaling (9) and depletion of B cells by anti-CD20 or anti-CD22-cal, have yielded variable results (10)(11)(12)(13)(14)(15). On the other hand, targeting T cells by anti-CD3 was also found to have limited effect in new-onset diabetic patients (16).…”

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confidence: 99%

Induction of Mixed Chimerism Depletes Pre-existing and De Novo–Developed Autoreactive B Cells in Autoimmune NOD Mice

et al. 2014

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Destruction of pancreatic islet b-cells in type 1 diabetes (T1D) is mainly mediated by autoimmune T and B lymphocytes. We reported that induction of major histocompatibility complex (MHC)-mismatched mixed chimerism reversed autoimmunity and reestablished thymic negative selection of autoreactive T cells in NOD mice, but it is still unclear how mixed chimerism tolerizes autoreactive B cells. The current studies were designed to reveal the mechanisms on how mixed chimerism tolerizes autoreactive B cells in T1D. Accordingly, mixed chimerism was induced in NOD mice through radiation-free nonmyeloablative anti-CD3/CD8 conditioning and infusion of donor CD4 + T cell-depleted spleen and whole bone marrow (BM) cells or through myeloablative total body irradiation conditioning and reconstitution with T cell-depleted BM cells from donor and host. Kinetic analysis of percentage and yield of preplasma and plasma B cells, newly developed B-cell subsets, and their apoptosis was performed 30-60 days after transplantation. Induction of MHC-mismatched mixed chimerism results in depleting host-type pre-existing preplasma and plasma B cells as well as augmenting apoptosis of immature transitional T1 B cells, including insulin-specific B cells in a donor B cell-dependent manner. Therefore, induction of MHC-mismatched mixed chimerism depletes pre-existing and de novo-developed autoreactive B cells.

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“…In patients with T1D, many immunologic strategies have been tested in phase II clinical trials; however, most of the results from these studies have been disappointing, with no single or combination treatment providing an unambiguous benefit in preserving β cell function. In a few studies, individuals have shown transient benefit (3)(4)(5)(6), while others have been without any observed benefit (7)(8)(9)(10). Still other immune interventions have ambiguous effects that do not meet their primary outcome measure, such as preservation of β cell function, but provide potential benefit based either on secondary outcome measures or mechanistic findings (11,12).…”

mentioning

confidence: 99%

Immune therapy for treating type 1 diabetes: challenging existing paradigms

Skyler¹

2014

J. Clin. Invest.

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C o m m e n t a r y9The search for effective immune interventions for type 1 diabetesType 1 diabetes (T1D) is considered to be an immune-mediated disease and thus potentially amenable to immune intervention (1). In animal models, a multitude of different immunologic approaches have been successful, including the use of single agents as well as a combination of agents selected for potential complementary effects (2). In patients with T1D, many immunologic strategies have been tested in phase II clinical trials; however, most of the results from these studies have been disappointing, with no single or combination treatment providing an unambiguous benefit in preserving β cell function. In a few studies, individuals have shown transient benefit (3-6), while others have been without any observed benefit (7-10). Still other immune interventions have ambiguous effects that do not meet their primary outcome measure, such as preservation of β cell function, but provide potential benefit based either on secondary outcome measures or mechanistic findings (11,12). Some phase III clinical trials have also been conducted, though none of these treatments have shown benefit. The lack of success in these clinical trials has resulted in many researchers in the field taking a step back in order to assess the challenges and the opportunities for immune intervention in T1D and rethink the approaches to be used. Interestingly, almost all of the clinical trials to date have enrolled subjects within the first 100 days after clinical diagnosis of T1D. It has been argued that the best responses are seen in patients who start immunotherapy as soon as possible after diagnosis of hyperglycemia; therefore, T1D ideally should be regarded as a "medical emergency," and immunologic treatment should be started within a few days of diagnosis (13).A number of studies in animal models suggest that more robust results may be obtained by combining immunemodulating agents that have expected complementary mechanisms (14). Only a few clinical studies to evaluate the use of combination therapy have been conducted, all of which failed to show benefit (15-17). One of the reasons that studies with combination therapy are lacking is that a demonstration that component therapies used together are safe is a requirement of regulating agencies. Moreover, for combination therapy, regulatory authorities ideally want each of the agents in the combined treatment to demonstrate individual efficacy. The few combination trials that have been allowed to go forward have used agents that have been used previously in combination in transplantation or some other setting. A paradigm-shifting combinationIn this issue, a study by Haller et al. examines the effects of a combination of lowdose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) on β cell function in patients with T1D (18). This combination has previously shown beneficial effect in preclinical diabetes models (19). Although the study by Haller et al. is a very small study (only 25 subjects, random...

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B-Lymphocyte Depletion With Rituximab and β-Cell Function: Two-Year Results

Cited by 223 publications

References 17 publications

Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes

Reestablishing T Cell Tolerance by Antibody-Based Therapy in Type 1 Diabetes

Induction of Mixed Chimerism Depletes Pre-existing and De Novo–Developed Autoreactive B Cells in Autoimmune NOD Mice

Immune therapy for treating type 1 diabetes: challenging existing paradigms

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