Complement factor and T-cell interactions during alloimmune inflammation in transplantation

Abstract

Complement factor and T‐cell signaling during an effective alloimmune response plays a key role in transplant‐associated injury, which leads to the progression of chronic rejection (CR). During an alloimmune response, activated complement factors (C3a and C5a) bind to their corresponding receptors (C3aR and C5aR) on a number of lymphocytes, including T‐regulatory cells (Tregs), and these cell‐molecular interactions have been vital to modulate an effective immune response to/from Th1‐effector cell and Treg activities, which result in massive inflammation, microvascular impairments, and fibrotic remodeling. Involvement of the complement‐mediated cell signaling during transplantation signifies a crucial role of complement components as a key therapeutic switch to regulate ongoing inflammatory state, and further to avoid the progression of CR of the transplanted organ. This review highlights the role of complement‐T cell interactions, and how these interactions shunt the effector immune response during alloimmune inflammation in transplantation, which could be a novel therapeutic tool to protect a transplanted organ and avoid progression of CR.

Hypoxia-induced complement dysregulation is associated with microvascular impairments in mouse tracheal transplants

“…As reported earlier, C3 in the first major active fragment, which has been reported to initiate microvascular associated injuries through the graft vascular-endothelial deposition [5,9,13,15,37,63]. In addition, endothelial deposition of C3 leads to the onset of vascular leakiness, microvascular congestion, thrombus formation, pulmonary edema and neutrophilic invasion of the microvasculature through the interaction of various inflammatory cells [15,64].…”

“…Herein, we demonstrated that early hypoxic state favors a cell-mediated inflammation, which proportionally triggers the downregulation of CD55, and thereby augments the uncontrolled release of active-C3, and Caspase-3 deposition on graft vascular endothelial cells. As reported in previous preclinical studies, alloimmune inflammation is characterized by a massive T cell infiltration (CD4 + and CD8 + ), associated proinflammatory cytokines, vascular deposition of CTL mediated Caspase-3 activation, which mutually take part in tissue and microvascular damage [9,15,37]. Our preliminary results also demonstrated a significant increase in early activation of HIF-1α mRNA (d6), followed by a massive increase in T cell infiltration and major proinflammatory cytokines (IL-2 and TNFα) during microvascular deterioration.…”

“…Role of complement and associated regulatory mechanism has been studied in ischemia/reperfusion injury and other associated pathological alterations during transplantation but a direct pathological impact of C3 activation and regulatory proteins is not well known during alloimmune inflammation post-transplantation. Activation of complement cascade release C3, C5 anaphylatoxins, and other toxic peptides, which play a decisive role in pathophysiological injuries during alloimmune inflammation [11][12][13][14][15]. To shield against the complementmediated injury, host tissues express several membraneanchored CRPs, which include decay-accelerating factor (DAF; CD55), membrane cofactor protein (MCP), complement receptor 1-related gene/protein y (Crry), complement receptor 1 (CR1) and CD59 [16,17].…”

Regulatory T cells mediated immunomodulation during asthma: a therapeutic standpoint

“…Tregs are potent immunosuppressive cells that are key in maintaining the homeostatic balance during dysregulated immune responses, which is a critical feature of asthma inflammation [69][70][71][72][73][74]. Tregs are generated in the thymus as a functionally mature T cell subset and in the periphery of naive T cells and are crucial in maintaining immunological unresponsiveness to self-antigens, and suppressing heightened immune responses destructive to the tissue during asthma inflammation [12,69,[75][76][77][78][79][80][81][82][83]. Tregs play a vital role in modulating and regulating immune responses by establishing the phase of immunotolerance and negating toxic inflammatory reactions, which are essential to maintain routine tissue repair as seen in several preclinical and clinical studies [60,62,84].…”

iPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants

“…Immunotolerance is a major immunological phase, which facilitates reparative microenvironment during transplantation, and plays a vital role to suppress alloimmune responses. A number of therapeutic options have been investigated to increase the number of regulatory T cells (Tregs) during allograft rejection, for example, through C5a blockade, stem cell therapy, and immune checkpoints, which potentially suppress infiltration of CD4 + T cells and antibody-mediated complement activation on vascular endothelial cells [1, 2, 4–8]. Cell-mediated immunotherapy is emerging as an alternative in single and combination therapies to rescue rejecting transplants.…”