Deficiency of C4 from Donor or Recipient Mouse Fails to Prevent Renal Allograft Rejection

Abstract

Complement effector products generated in the transplanted kidney are known to mediate transplant rejection, but which of the three main activation pathways of complement trigger this response is unclear. Here we assessed the role of the classical and lectin pathways by studying the common component C4 in mouse kidney transplant rejection. We transplanted wild-type or C4-null H-2 b donor kidneys into H-2 k or H-2 d recipients, or vice-versa, to assess the roles of donor kidney and recipient expression of complement. Intragraft C4 gene expression rose substantially during rejection. However, we found no significant association between graft acceptance and the presence of C4 in either the donor kidney or recipient mouse. At the time of rejection, we found no significant differences in alloantibody response in the different groups. Tubular deposition of C3 to C9 occurred regardless of the absence or presence of C4 in either the donor or recipient mouse, indicating that C4 was dispensable for complement activation at this site. These data suggest that complement activation and renal allograft rejection are independent of the classical and lectin pathways in these models, implying that in the absence of these pathways the alternative pathway is the main trigger for complementmediated rejection.

Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury

“…The lectin pathway mediated C4-bypass may also explain the lack of a protective phenotype of C4 deficiency in our model of MIRI, as well as in a previously described model of renal allograft rejection (39). In contrast, we have recently demonstrated a significant protective phenotype of MASP-2 −/− mice in models of renal transplantation (40).…”

Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a–C3aR interaction

“…29 In contrast, C4-deficient DCs (in this study) and macrophages (our previous study) appear to function normally in alloreactive T-cell stimulation, and C4-deficient kidney allografts are rejected normally. 13,30 These results suggest that, in vivo, factors capable of triggering the alternative pathway with subsequent cleavage of C3 would be sufficient to enhance APC function in T-cell priming. The cleavage of C3 leads to the generation of complement effector products, among which C3a and C5a are potent proinflammatory mediators and cell activators, exerting their functions through binding to specific receptors with nanomolar affinity.…”

Myeloperoxidase Is Critically Involved in the Induction of Organ Damage after Renal Ischemia Reperfusion

“…Complement proteins contribute to the development of I/Rinduced organ injury. 6,31,47 Predominantly the activation of the lectin 30,31 and alternative pathway 48 as well as the formation of the membrane attack complex (MAC) 49,50 and small cationic proteins (C3a, C4a, and C5a), known as anaphylatoxins, have been shown to be involved in I/R-induced tissue injury. 6,26 The deposition of early complement-activating proteins after 2 or 24 hours of reperfusion was similar between Mpo Ϫ/Ϫ and WT treated mice.…”