PLATELET INVOLVEMENT IN EXPERIMENTAL IMMUNE COMPLEX-MEDIATED GLOMERULONEPHRITIS IN THE NONHUMAN PRIMATE

Abundant glomerular platelet deposition is a hallmark of certain anima l models of immune complex (IC)-mediated glomerulonephritis (GN). By c ontrast, conspicuous platelet deposition is uncommon in the IC-GN seen in humans. This could result from intrinsic differences between human and animal platelets, which are known to be present. To assess whethe r abundant glomerular platelet deposition can occur in humans with IC- GN, the present studies were undertaken in nonhuman primates (cynomolg us monkeys, CYN), with active experimental IC-GN induced by 12 weeks o f daily intravenous infusion of bovine gamma globulin (BGG). CYN are a ppropriate for these studies because, like humans, CYN platelets do no t express the C3b receptor but do express receptors for the Fc region of IgG (FcRgammaII). Furthermore, in this model of IC-GN, which is ind istinguishable from IC-GN seen in humans, it is possible to time the b iopsy to coincide with a period of peak activity of the GN. The presen t studies proceeded as follows: ten CYN were studied before and after intravenous infusion of BGG sufficient to achieve conditions near anti gen/antibody equivalence for circulating precipitating antibody to BGG . The infusion of BGG, which was given over 10 minutes, resulted in an acute reduction in circulating platelets (mean 43% +/- 5 SE, P < 0.00 1). However, renal biopsies performed before and five minutes after th e acute reduction in circulating platelets showed that relatively few of the platelets removed from the circulation lodged in glomeruli (pla telets/glomerular cross section: 0.2 +/- 0.06 before BGG vs. 0.88 +/- 0.31 after BGG, P = 0.035). In five of the CYN studied under the above protocol, autologous platelets were labeled with In-111 In and reinfu sed into the CYN just prior to the BGG infusion. These studies confirm ed the paucity of platelet deposition in kidney but showed major uptak e of the In-111-labeled platelets by liver and spleen (mean +/- SE In- 111 In CPM/mg of tissue: kidney cortex 18 +/- 8, liver 132 +/- 42, and spleen 808 +/- 127, P = 0.038, comparing kidney to liver or spleen by paired t-test). Thus, the platelets removed from the circulation were taken up at the sites which are also the principal sites of IC uptake (liver and spleen), and over the time interval that coincides with th e period of maximum uptake of IC by liver and spleen, after BGG infusi on. In vitro studies, discussed herein, showed that BGG anti-BGG IC bi nd to CYN platelets via FcRgammaII. Thus, we suggest that, in vivo, ci rculating IC become bound to platelet FcRgammaII and the platelet-IC c omplex is cleared from the circulation, mainly by uptake by liver and spleen. Such a mechanism would divert platelets, activated by liption of IC, from sites of IC-mediated injury such as the kidney. Such a mec hanism would spare the kidney from platelet-induced injury. In primate s with an active experimental IC-GN, which is comparable to GN seen in humans, platelets show little tendency to lodge in glomeruli. Instead , primate platelets appear to be primarily involved in the clearance o f IC from the circulation. These observations suggest that, with respe ct to the pathogenesis of IC-GN, primate platelets may play a role tha t is different from that of rodent platelets.