Effect of Rosiglitazone in MHC Class Ii Disparate Cardiac Allograft Rejection

Innate Immunity and Resistance to Tolerogenesis in Allotransplantation

“…Upon activation, they release large amounts of pro-inflammatory cytokines such as TNFα, IL-12 IL-1, and IL-6, which promote both innate and adaptive immune responses (Geissmann et al, 2010). Macrophages play a key role in the induction of antibody dependent cellular cytotoxic (ADCC) reactions leading to the phagocytosis of opsonized allogeneic target cells (Unanue and Allen, 1986; Rocha et al, 2003; Li, 2010). During acute inflammation, while PMNs are typically the first phagocytes infiltrating allografts, macrophages are usually involved in secondary stages of inflammation during which they remove aged PMNs via a mechanism involving PECAM-1 (CD31) as well as necrotic cells and cellular debris (Davies et al, 1993; Wu et al, 2007b; Roh et al, 2010; Wu and Madri, 2010).…”

“…In addition to their role in innate immunity, macrophages process, and present alloantigens to CD4 + T cells in a MHC class II context thus initiating T cell-mediated responses and rejection (Beller and Unanue, 1980; Lu et al, 1981; Unanue and Allen, 1986; Unanue, 2002; Calderon et al, 2006). Some observations indicate that, in stable transplants, macrophages can convert otherwise harmless lymphocytes into aggressive ones and cause rejection, thereby controlling the cytopathic features of cellular infiltrates in solid organ transplants (Li, 2010). Likewise, some studies have shown the beneficial effects of blockage of the macrophage-migration inhibitory factor (MIF) on the pathogenesis of allografts including the reduction of obstructive bronchiolitis after lung transplantation (Fukuyama et al, 2005; Javeed and Zhao, 2008).…”

“…Altogether, the majority of transplant immunologists have focused their efforts on the deletion and/or inactivation of alloreactive T and B cells, pre-transplantation. On the other hand, recent studies have proven beyond doubt that innate immunity is also an essential element of both acute and chronic rejection of allo- and xenografts (LaRosa et al, 2007; Alegre et al, 2008a,b; Alegre and Chong, 2009; Li, 2010; Goldstein, 2011; Murphy et al, 2011). Innate immune responses are initiated as a consequence of reperfusion injury, inflammation, tissue damage, and presumably microbial infections occurring at the time of transplantation (Figure 1).…”