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Inhibition of Complement: Tackling of Both Innate and Adaptive Immune Responses to Dampen Rejection

Ambadapadi, Sriram PhD

doi: 10.1097/TP.0000000000001624

This commentary puts the findings of Zhu et al on complement inhibition in heterotopic hind limb transplants in mice in a broader context and points out the need for research to move the concept of complement inhibition to the clinic.

1 The Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ.

Received 2 December 2016. Revision received 17 December 2016.

Accepted 22 December 2016.

The authors declare no funding or conflicts of interest.

Correspondence: Sriram Ambadapadi, PhD, 1001S McAllister Ave Biodesign Institute, A220DB Tempe, AZ 85287. (

Immunosuppression regimen that is necessary to keep rejection in check has been known to have its adverse effects, especially when prolonged and sometimes lifelong usage is necessary, as in the case of some transplants. Opportunistic Cytomegalovirus1 and multidrug resistant Pseudomonas2 infections have been reported to be accompanying immunosuppression along with oft noted metabolic dysfunctions. The histological heterogeneity of a vascular composite allograft (VCA) has been suggested to elicit different levels of immunogenicity from its components with skin being the most immunogenic followed by bone, muscle and so on.3 It is evidently a more complex immune milieu that one has to deal with in the VCA compared with solid organ transplants. Nevertheless, the lessons learnt from organ transplantation with regard to the principle actors in the recurrent acute rejection episodes and chronic rejection can be used in tackling some of the same problems with VCA. The involvement of innate immunity in the ischemia-reperfusion injury, one of the major causes of inflammation in rejection, is being studied in tandem with the activation of adaptive immunity with T cell mediation and the involvement of major histocompatibility complex incompatibility to better understand the broad underlying mechanisms leading to the immunogenicity.

Deservedly, attention is being paid to the complement system which seems to act in the intersection of innate and adaptive immunity and drives inflammatory responses both by opsonization that leads to lysis of pathogens and also by facilitating the secretion of proinflammatory cytokines (Figure 1).4 Complement component 3 (C3), the common product of classical, lectin, and alternate pathways of complement activation leads to the lysis of its pathogenic target, mediated by the downstream products of C3. The cleavage products of C3 and C5, namely, C3a and C5a, respectively are proinflammatory and contribute to cytokine production, which could broadly be classified as an innate immune response. It has been shown recently5 that classical pathway of complement activation on endothelial cell surface not only contributes to endothelial cell activation but also contributes to generation of chemoattractant C3a and C5a that exacerbate the leukocyte infiltration.

This multidimensional nature of complement system has been elegantly characterized in the work of Zhu et al6 in an article published in this issue. Atkinson and colleagues7 have previously shown that a Complement receptor 2 (CR2) targeted inhibitor of C3 activation, CR2-Crry, had better bioavailability and efficacy than Crry-Ig and did not impair the host immunity to infection at the same time, in a mouse model of intestinal ischemia/reperfusion injury. In the current study being highlighted in this issue Zhu et al assessed the effect of complement inhibition in heterotopic hind limb transplants in mice and compared this pan-complement inhibition with C3 deficiency. Studies designed to understand the role of anaphylatoxins C3a and C5a in VCA were also presented where the recipients were deficient in C3aR and C5aR. The observations that pan-complement inhibition by CR2-Crry and C3 deficiency confer better protection from ischemia/reperfusion related inflammation in VCA and significantly lower the characteristics of rejection in histopathology, complement deposition, inflammatory cell influx, and P-selectin expression compared to C3aR−/−C5aR−/− point toward the fork in the road that C3 activation takes where one branch leads to innate immune responses and the other to adaptive immunity pathways.

Furthermore, the authors observed that the dual therapy with CR2-Crry and a subtherapeutic dose of cyclosporine A was significantly better at increasing median survival in the VCA recipients compared not only to the PBS controls but also to the groups of mice that received only either Cr2-Crry or Cyclosporine A. This is a welcome finding considering the effects of immunosuppression on the patient's ability to fight infection as mentioned above. Presented in the study also are data concerning the histology and immunohistology, complement deposition and flow cytometric analysis of splenic cell populations that buttress the hypothesis proposed. Going forward, understanding the mechanism for enhanced activity with C3 inhibition, unequivocally will also help judge the clinical benefits and weigh the pros and cons of therapeutic use of complement inhibition. Efforts in this direction are already underway in the form of clinical trial and preclinical studies of recombinant human fusion proteins and the studies on complement inhibition will certainly enhance the current knowledge.

With the recent reports of complement component 5 (C5) inhibition with eculizumab providing an efficient way to combat antibody mediated rejection8 and atypical hemolytic uremic syndrome9 after kidney transplants, these are exciting times to be following the ongoing preclinical and clinical efforts in complement inhibition. The current knowledge of complement inhibition, particularly the clinical utility of plasma-derived C1 inhibitor are reviewed recently10 and make for an engaging reading. Improvements in immunosuppression are welcome whether the transplant is conducted in a life threatening situation as is the case in most of the solid organ transplants or in the case of VCA where the patient usually elects the procedure for the physical and psychological boost it provides.

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