Showing papers by "William G. Austen published in 2002"

Functional Activity of Natural Antibody is Altered in Cr2-Deficient Mice

Abstract: The major source of natural IgM Abs are B-1 cells, which differ from conventional B cells in their anatomic location, cell surface phenotype, restricted usage of particular V H genes and limited use of N-region addition during V-D-J rearrangement. The origin of B-1 cells is unclear. However, they are capable of self-renewal and their development is sensitive to signaling via the B cell receptor, as genetic defects that impair the strength of the signal often result in limited development. These findings suggest that B-1 cells require either an intrinsic signal, or contact with Ag, for positive selection and expansion and/or maintenance in the periphery. In support of interaction with cognate Ag, deficiency in the complement receptors CD21/CD35 results in a 30–40% decrease in the CD5 + B-1 population. To determine whether this reduction reflects a loss of certain specificities or simply a proportional decline in the repertoire, we examined peritoneal B cells isolated from Cr2 + and Cr2 def mice for recognition of a B-1 cell Ag, i.e., phosphatidylcholine, and assayed for injury in an IgM natural Ab-dependent model of reperfusion injury. We found a similar frequency of phosphatidylcholine-specific CD5 + B-1 cells in the two strains of mice. By contrast, the Cr2 def mice have reduced injury in the IgM-dependent model of reperfusion injury. Reconstitution of the deficient mice with pooled IgM or adoptive transfer of Cr2 + peritoneal B cells restored injury. These results suggest that complement receptors CD21/CD35 are important in maintenance of the B-1 cell repertoire to some, but not all, specificities.

Recombinant soluble P-selectin glycoprotein ligand 1 moderates local and remote injuries following experimental lower-torso ischaemia.

Abstract: Background: A central role for the polymorphonuclear leucocyte (PMN) in skeletal muscle ischaemia–reperfusion has been demonstrated by the observation that PMN depletion reduced local and remote pulmonary vascular permeability. This study investigated the role of recombinant soluble P-selectin glycoprotein ligand–immunoglobulin fusion protein (rPSGL-Ig), a P- and E-selectin antagonist, in moderating injury. Methods: Mice underwent 2 h of hindlimb ischaemia and 3 h of reperfusion. Muscle and lung vascular permeability index (PI) was assessed by extravasation of 125I-radiolabelled albumin. Lung myelo peroxidase (MPO) activity was also measured. Results: In mice treated with rPSGL-Ig 1 mg/kg before reperfusion (n = 12) muscle PI was reduced by 40 per cent, whereas it was moderated by 20 per cent in animals treated 30 min after reperfusion (n = 15). Lung PI in mice treated with rPSGL-Ig before (n = 12) and 30 min after (n = 15) reperfusion was reduced by over 99 and 98 per cent respectively. Lung MPO activity in mice treated with rPSGL-Ig before (n = 10) and 30 min after (n = 12) reperfusion was reduced by 68 and 58 per cent respectively. Treatment with rPSGL-Ig 1 h after reperfusion, or with m20ek.Fc 1 mg/kg (n = 9; negative control for rPSGL-Ig which is inactive for selectin binding) before reperfusion failed significantly to moderate local or remote organ injury. Conclusion: Selectin blockade moderated local skeletal muscle and remote lung injury following hindlimb ischaemia–reperfusion. Significantly, delayed antiselectin therapy also decreased injury. © 2001 British Journal of Surgery Society Ltd