Influence of complement on the allospecific antibody response to a primary vascularized organ graft

Abstract

The induction of antibody responses against T cell-dependent antigens has been reported to be influenced by complement. We therefore asked if the primary induction of alloantibodies against transplantation antigens, an important determinant of transplant outcome, is complement sensitive and whether this has functional implications. We transplanted rat kidney allografts into fully major histocompatibility complex-mismatched recipients, in which complement activation was inhibited by daily injection of soluble recombinant human complement receptor type 1 (sCR1). Control allograft recipients were injected with saline. Animals in the control group showed a marked antibody response against donor-specific antigens and an increase in the proportion of activated B and T splenocytes by day 5 after transplantation. Complement-inhibited rats showed a reduced level of antibody binding on target cells sharing the same histocompatibility antigens as the donor strain (p < 0.001), and a reduced level of activated splenic B (p < 0.01) and T (p < 0.01) cells. In a functional assay, the plasma of complement-inhibited rats showed reduced cytotoxic activity against donor-specific cells, and their grafts contained less bound antibody than controls. Analysis beyond 6 days was obscured due to the development of antibodies against sCR1. We conclude that complement activation facilitates the induction of the alloantibody response. Sparing of vascular injury and prolongation of graft survival, previously reported in complement-inhibited rats (Pratt J. R. et al., Am. J. Path. 1996, 149: 2055), could therefore be due to down-regulation of the B cell response as well as reduced complement-dependent cytotoxicity. Inhibition of complement may provide an ancillary approach to the prevention of allospecific antibody formation and the prolongation of allograft survival in primary kidney grafting.

Complement activation is critical for placental ischemia-induced hypertension in the rat

“…The sCR1 reduction in CH 50 at day 19 was significant but not as marked as some previously published studies. sCR1 effectiveness in inhibiting total hemolytic complement activity may be limited by the 5 day treatment course in our study, consistent with the observations made by Pratt et al (Pratt et al, 1997) who demonstrated rat anti-human sCR1 antibody production after several days that limits effectiveness. sCR1 is also known to bind C1q (Klickstein et al, 1997) and MBL (Ghiran et al, 2000) and thus may affect processes beyond inhibition of the complement cascade at the level of the C3 and C5 convertases.…”

sCR1sLeX reduces lung allograft ischemia–reperfusion injury but does not ameliorate acute rejection

“…Alloantibody response against donor-specific antigens and the proportion of activated B and T splenocytes after transplantation were decreased by complement inhibition [18], endothelial and vascular injury was reduced, and graft survival in experimental kidney allotransplantation was prolonged [14].…”

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

“…The generation of activated complement anaphylatoxins and opsonins further propagates cellular and molecular signaling, and thus, initiates massive immune inflammation through the cross‐interactions with T cells, B cells, macrophages, neutrophils, dendritic cells, and accelerates fibrosis and rejection of transplanted graft . After activation, all the three complement pathways converge at C3 formation, which further leads to the induction of a series of alloimmune responses to grafted tissue . The activation of the complement cascade and its potential role in innate immunity have been proven crucial in complement‐mediated injuries to graft during rejection, and as reported in various preclinical and clinical transplant studies, activated complement factors (C3a, C3d, C5a, C5b, and C4d) have been associated with number of graft injuries, which include acute inflammation, microvascular loss/ischemia, and progression of fibrosis .…”

“…14,17,24,36,37 After activation, all the three complement pathways converge at C3 formation, 4,17 which further leads to the induction of a series of alloimmune responses to grafted tissue. 38,39 The activation of the complement cascade and its potential role in innate immunity have been proven crucial in complement-mediated injuries to graft during rejection, and as reported in various preclinical and clinical transplant studies, activated complement factors (C3a, C3d, C5a, C5b, and C4d) have been associated with number of graft injuries, which include acute inflammation, microvascular loss/ischemia, and progression of fibrosis. 14,17,40,41 Activation and deposition of complement mediators have been associated with both T cell-mediated and antibody-mediated transplantation injuries.…”