Inhibition of ICAM-1/LFA-1 Interactions Prevents B-Cell-Dependent Anti-CD45RB-Induced Transplantation Tolerance

Huang, Xiaolun; Moore, Daniel J.; Mohiuddin, Mohammad; Lian, Moh-Moh; Kim, James I.; Sonawane, Samsher; Wang, Jing; Gu, Yi; Yeh, Heidi; Markmann, James F.; Deng, Shaoping

doi:10.1097/tp.0b013e3181663422

Cited by 28 publications

(21 citation statements)

References 36 publications

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“…Antibodies to CD45RB exert important effects both centrally and in the periphery, as we and others have previously characterized (18, 19, 31–35). An anti-human CD45RB antibody has been developed and demonstrated to have preliminary efficacy in a monkey kidney transplant model (36).…”

Section: Discussionmentioning

confidence: 74%

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

et al. 2011

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The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (Tregs); thymectomy or Treg depletion abrogated tolerance restoration. The aging of the immune system (“immune senescence”) is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.

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Section: Discussionmentioning

confidence: 74%

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

et al. 2011

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“…Anti-CD45RB induces robust, antigen-specific transplantation tolerance that is absolutely dependent on the presence of B lymphocytes (4,5). As we have previously reported, the mechanism requires CD45RB expression on the surface of B lymphocytes, suggesting that antibody treatment may activate the regulatory potential of B lymphocytes or induce the differentiation of regulatory B cells (4).…”

Section: Discussionmentioning

confidence: 99%

An Unexpected Counter-Regulatory Role of IL-10 in B-Lymphocyte-Mediated Transplantation Tolerance

Zhao

Moore

Lee

et al. 2010

American Journal of Transplantation

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Monoclonal antibody against the CD45RB protein induces stable transplantation tolerance to multiple types of allograft. We have previously established that this tolerance protocol relies on the regulatory function of B lymphocytes for its effect. B lymphocytes have also been reported to participate in immune regulation in several other settings. In most of these systems, the regulatory function of B lymphocytes depends on the production of IL-10. Therefore, we investigated the role of IL-10 in the anti-CD45RB model of B-cell-mediated transplantation tolerance. Surprisingly, using antibody-mediated neutralization of IL-10, IL-10-deficient recipients and adoptive transfer of IL-10-deficient B lymphocytes, we found that IL-10 actually counter-regulates tolerance induced by anti-CD45RB. Furthermore, neutralization of IL-10 reduced the development of chronic allograft vasculopathy compared to anti-CD45RB alone and reduced the production of graft reactive alloantibodies. These data suggest that the participation of regulatory B lymphocytes in transplantation tolerance may be distinct from how they operate in other systems. Identifying the specific B lymphocytes that mediate transplantation tolerance and defining their mechanism of action may yield new insights into the complex cellular network through which antigen-specific tolerance is established and maintained.

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“…We established the importance of direct contact between HBC and CD11bϩMC and implicated CD11b and STAT3 as mediators of HBC CD80 loss. We speculate that CD11b on CD11bϩMC interacts with ICAM-1 (CD54) expressed by B cells [30,51,52]. Interestingly, CD11b blockade has been shown to reverse MDSC-mediated suppression of T cells [25], although it is not clear whether CD11bϩMC use similar mechanisms for T and B cell suppression.…”

Section: Discussionmentioning

confidence: 99%

Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+CD11b+ myeloid cells

Thorn

Point

Burga

et al. 2014

Journal of Leukocyte Biology

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LM escape immune surveillance, in part, as a result of the expansion of CD11bϩMC, which alter the intrahepatic microenvironment to promote tumor tolerance. HBC make up a significant proportion of liver lymphocytes and appear to delay tumor progression; however, their significance in the setting of LM is poorly defined. Therefore, we characterized HBC and HBC/CD11bϩMC interactions using a murine model of LM. Tumor-bearing livers showed a trend toward elevated absolute numbers of CD19ϩ HBC. A significant increase in the frequency of IgM lo IgD hi mature HBC was observed in mice with LM compared with normal mice. HBC derived from tumor-bearing mice demonstrated increased proliferation in response to TLR and BCR stimulation ex vivo compared with HBC from normal livers. HBC from tumor-bearing livers exhibited significant down-regulation of CD80 and were impaired in inducing CD4 ϩ T cell proliferation ex vivo. We implicated hepatic CD11bϩMC as mediators of CD80 down-modulation on HBC ex vivo via a CD11b-dependent mechanism that required cellto-cell contact and STAT3 activity. Therefore, CD11bϩMC may compromise the ability of HBC to promote T cell activation in the setting of LM as a result of diminished expression of CD80.

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Inhibition of ICAM-1/LFA-1 Interactions Prevents B-Cell-Dependent Anti-CD45RB-Induced Transplantation Tolerance

Cited by 28 publications

References 36 publications

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

Inhibition of Transplantation Tolerance by Immune Senescence Is Reversed by Endocrine Modulation

An Unexpected Counter-Regulatory Role of IL-10 in B-Lymphocyte-Mediated Transplantation Tolerance

Liver metastases induce reversible hepatic B cell dysfunction mediated by Gr-1+CD11b+ myeloid cells

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