Resistance to anti-CD45RB-induced tolerance in NOD mice: mechanisms involved

Moore, Daniel J.; Huang, Xiaolun; Lee, Major K.; Lian, Moh-Moh; Chiaccio, Meredith; Chen, Haiying; Koeberlein, Brigitte; Zhong, Robert; Markmann, James F.; Deng, Shaoping

doi:10.1111/j.1432-2277.2004.tb00440.x

Cited by 22 publications

(14 citation statements)

References 54 publications

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“…42,43 Anti-RB treatment is useful as an immunotherapeutic agent and induces transplant tolerance. 39,[44][45][46][47] It must be stressed that B cells play a critical role in these processes. 48 Therefore additional studies into the impact of CD45RB ligation on the surface of B cells are needed.…”

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Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Jackson

Harp

Patel

et al. 2009

Blood

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We previously reported that RO ؉ expression correlated with increased mutation, activation, and selection among human germinal center (GC) B cells. Here, we subdivided human tonsillar B cells, including IgD ؊ CD38 ؉ GC B cells, into different fractions based on RB expression. Although each subset contained RB ؉ cells, when used as an intrasubset marker, differential RB expression effectively discriminated between phenotypically distinct cells. For example, RB ؉ GC B cells were enriched for activated cells with lower AID expression. RB inversely correlated with mutation frequency, demonstrating a key difference between RB-and RO-expressing GC B cells. Reduced RB expression during the transition from pre-GC (IgM ؉ IgD ؉ CD38 ؉ CD27 ؊ ) to GCB cells was followed by a dramatic increase during the GC-to-plasmablast (IgD ؊ CD38 ؉؉ CD27 ؉ ) and memory (IgD ؊ CD38 ؊ CD27 ؉ ) transition. Interestingly, RB ؉ GC B cells showed increased signs of terminal differentiation toward CD27 ؉ post-GC early plasmablast (increased CD38 and RO) or early memory IntroductionImmune function is uncompromisingly governed by at least 3 interdependent principles including recognition, effector function, and transition. Early naive B and T cells that successfully bind foreign antigen become activated and undergo developmental transition toward more mature, faster responding memory subsets. In contrast, lymphocytes that bind self-antigen in the periphery are usually counterselected against and undergo a different type of transition, one toward apoptosis or anergy. Ineffectual negative selection against self-specific B cells has been associated with the development of autoimmune and neoplastic diseases. Unfortunately, potential factors responsible for the redirection or abrogation of transitions toward cell death and anergy have not been conclusively determined. Antibody sequence analyses revealed that B cells participating in autoreactive responses are often mutated and show signs of selection for self-antigen. 1,2 This suggests that somatic hypermutation (SHM) during proliferation and activationbased transitions in the dynamic germinal center reaction may play a role (whether direct or indirect) in disease pathogenesis.We therefore sought to develop an expedient approach that would allow for the reproducible identification of B-cell populations that exist at different transitional stages based on their states of activation, SHM-dependent diversification, and developmental progression toward adjacent downstream subsets. Delineating how surface marker profiles change as B cells transition between key stages (especially when immunoregulatory markers such as CD45 protein tyrosine phosphatase are included in such profiles) should increase our understanding of B-cell development and ultimately how to circumvent dysregulated processes that could lead to disease.Over the past 3 decades, our research laboratory has investigated multiple aspects of human B-cell development and the molecular processes that collectively shape the peripheral BCR repertoi...

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confidence: 99%

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Jackson

Harp

Patel

et al. 2009

Blood

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“…Initial studies indicated a role of tolerogenic dendritic cells in this model (12). In addition, we have recently studied the effect of anti-CD45RB therapy in NOD mice and found that NOD mice are resistant to anti-CD45RB-induced transplant tolerance, even in the absence of autoimmunity (13). Because of the critical role played by B lymphocytes as APCs in autoimmune disease (14), we hypothesized that B cells may play a requisite role in tolerance induced by anti-CD45RB.…”

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Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Deng

Moore

Huang

et al. 2007

The Journal of Immunology

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Selective interference with the CD45RB isoform by mAb (anti-CD45RB) reliably induces donor-specific tolerance. Although previous studies suggest participation of regulatory T cells, a mechanistic understanding of anti-CD45RB-induced tolerance is lacking. We report herein the unexpected finding that tolerance induced by this agent is not established in B cell-deficient mice but can be recovered by preemptive B lymphocyte transfer to B cell-deficient hosts. Using B cells from genetically modified donors to reconstitute B cell-deficient recipients, we evaluate the role of B lymphocyte-expressed CD45RB, T cell costimulatory molecules, and the production of Abs in this novel tolerance mechanism. Our data document an Ab-induced tolerance regimen that is uniquely B lymphocyte-dependent and suggest mechanistic contributions to tolerance development from the B cell compartment through interactions with T cells.

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“…Consistent with this process, islet-specific autoantibodies, particularly ones reactive with insulin, are recognized as sensitive indicators of disease (20 -26). To date, tolerance-inducing therapies initiated after the appearance of IgG anti-insulin autoantibodies fail to halt disease progression (27,28). Thus, earlier predictive methods are required to maintain or restore lymphocyte tolerance before ␤ cell destruction.…”

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Multiple Germline κ Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice

Woodward

Thomas

2005

The Journal of Immunology

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The highly selective nature of organ-specific autoimmune disease is consistent with a critical role for adaptive immune responses against specific autoantigens. In type 1 diabetes mellitus, autoantibodies to insulin are important markers of the disease process in humans and nonobese diabetic (NOD) mice; however, the Ag-specific receptors responsible for these autoantibodies are obscured by the polyclonal repertoire. NOD mice that harbor an anti-insulin transgene (Tg) (VH125Tg/NOD) circumvent this problem by generating a tractable population of insulin-binding B cells. The nucleotide structure and genetic origin of the endogenous κ L chain (Vκ or IgL) repertoire that pairs with the VH125Tg were analyzed. In contrast to oligoclonal expansion observed in systemic autoimmune disease models, insulin-binding B cells from VH125Tg/NOD mice use specific Vκ genes that are clonally independent and germline encoded. When compared with homologous IgL genes from nonautoimmune strains, Vκ genes from NOD mice are polymorphic. Analysis of the most frequently expressed Vκ1 and Vκ9 genes indicates these are shared with lupus-prone New Zealand Black/BINJ mice (e.g., Vκ1–110*02 and 9–124) and suggests that NOD mice use the infrequent b halpotype. These findings show that a diverse repertoire of anti-insulin B cells is part of the autoimmune process in NOD mice and structural or regulatory elements within the κ locus may be shared with a systemic autoimmune disease.

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Resistance to anti-CD45RB-induced tolerance in NOD mice: mechanisms involved

Cited by 22 publications

References 54 publications

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Key developmental transitions in human germinal center B cells are revealed by differential CD45RB expression

Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes

Multiple Germline κ Light Chains Generate Anti-Insulin B Cells in Nonobese Diabetic Mice

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