Transplantation of C3H hearts into either ICAM-1?/? (n=6, triangle) or LFA-1?/? (n=6, diamond) recipients prospects to rejection in a routine fashion indicating the immunocompetence of the recipients

Transplantation of C3H hearts into either ICAM-1?/? (n=6, triangle) or LFA-1?/? (n=6, diamond) recipients prospects to rejection in a routine fashion indicating the immunocompetence of the recipients. transfer of control splenocytes to VP3.15 B-cell-deficient recipients permitted anti-CD45RB-induced tolerance, whereas transfer of ICAM?/? cells was unable to support tolerance induction. Conclusions Expression of ICAM-1 by B lymphocytes and conversation with LFA-1 form a central aspect of transplantation tolerance induced by anti-CD45RB therapy. These data further elucidate the cellular mechanisms used by B lymphocytes in the induction of transplantation tolerance. Keywords: Tolerance, Transplantation, ICAM, LFA-1, Anti-CD45RB The success of transplantation for numerous life-threatening illnesses is currently predicated on the efficacy of immunosuppressive therapies. Given the toxicities of these regimens, there is a strong impetus to develop new strategies that induce permanent donor-specific tolerance. Despite the great theoretical advantages of such therapies, translating them into the clinical setting remains a significant challenge. A better understanding of the mechanistic underpinnings of induced tolerance may facilitate this transition and may also reveal tolerance-adverse interactions that could occur in the setting of polypharmacy. Monoclonal antibody therapy against the CD45RB molecule is an attractive target, given the short course of therapy needed for tolerance induction and the growing body of literature elucidating the mechanism of action of this reagent VP3.15 (1C4). Previous studies have exhibited the induction of donor-specific regulatory T cells, the importance of cytotoxic T lymphocyte antigen 4 (CTLA-4), the modulation of peripheral T cell ratios, and the requisite role of the thymus (5C9). Unexpectedly, we have also recently exhibited an absolute requirement for B lymphocytes in this model of transplantation tolerance (10). Our finding that B cells are NOTCH2 required for anti-CD45RB-mediated tolerance has important implications, given a recent surge in desire for B-cell-depleting immunotherapies in the settings of both transplantation and autoimmunity. B lymphocytes are the most numerous antigen presenting cells and have the unique capacity to concentrate circulating antigen several hundred fold through the surface Ig receptor, a capability that suggests a prominent role in indirect allopresentation. The requirement for B cell participation in tolerance induction opens a number of new investigational opportunities. If this tolerance-promoting pathway can be discerned, it is possible that it could be replaced VP3.15 by tailored pharmacotherapy or that this pathway in recipient B cells could be specifically enhanced during tolerance induction. Moreover, given the role of regulatory T cells in anti-CD45RB and other immunotherapies, there may be important insights into B cell-Treg interactions. During our prior investigation, we have exhibited that treatment with anti-CD45RB induces B cells to up-regulate CD54 (intercellular adhesion molecule [ICAM]-1) during therapy (11). Because the ICAM-1 adhesion molecule is usually important for lymphocyte migration and may also have co-stimulatory function, we have extended these studies to determine the function of ICAM-1/lymphocyte function-associated VP3.15 antigen-1 (LFA-1) interactions in tolerance induced by anti-CD45RB. Herein, we statement that this pathway is also required for long-term tolerance induction. MATERIALS AND METHODS Mice Mice (C57BL/6, C3H, B6.ICAM-1?/?, B6.LFA-1?/?, and B6.test). Similar analysis for draining and para-aortic lymph nodes also reveals a significant increase in ICAM-1 expression (test). Combination Therapy With Anti-CD45RB and Blockade of ICAM-1/LFA-1 Conversation Prospects to Disruption of Tolerance Induction Given the strong association of CD54 up-regulation with CD45RB-directed treatment, we decided whether this switch played a positive or unfavorable role in the tolerance process. Because ICAM-1 itself is usually a potent co-stimulatory molecule and antibody against ICAM-1 has also been used successfully to induce tolerance (13C16), we considered whether up-regulation of the ICAM molecule may inhibit tolerance induction because anti-CD45RB fails to induce tolerance in about 30% of treated recipients in most published series. We hypothesized that blockade of the ICAM-1/LFA-1 conversation could enhance VP3.15 anti-CD45RB-mediated tolerance induction, and therefore, decided whether antibody-mediated disruption of the LFA-1/ICAM-1 conversation would enhance or disrupt tolerance induced by anti-CD45RB in a fully allogeneic C3H to B6 cardiac transplant model. As can be seen.