Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies.

Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans.

Immune correlate study on human Schistosoma japonicum in a well-defined population in Leyte, Philippines: II. Cellular immune responses to S. japonicum recombinant and native antigens.

Cellular immune responses to specific Schistosoma japonicum recombinant and native antigens were investigated in a defined study population of 155 individuals in the Philippines, where data collected from a 3-year observation of exposure, infection and reinfection pattern were used to categorically classify putative 'resistant' and 'susceptible' individuals. Using peripheral blood mononuclear cells (PBMC) of individuals enrolled in the study, in vitro lymphocyte proliferation and cytokine (IFN-gamma, IL-5 and IL-10) production in response to defined recombinant antigens (97 kDa paramyosin, 22 kDa tegumental antigen, 37 kDa glyceraldehyde-3-phosphate dehydrogenase, 14 kDa fatty acid binding protein and 28 kDa gluthathione-S-tranferase) and native antigen soluble worm antigen preparation (SWAP) were measured. Cellular responses to the recombinant and SWAP antigens suggest that Th1 type of response appear to be important in predicting resistance in this population. Of the five recombinant antigens tested, rPMY induced significant levels of IFN-gamma. The production of IL-10, a Th2-type cytokine was strongly implicated in immune regulation. Of importance was the evidence found for SWAP and rPMY induced IFN-gamma responses in predicting 'resistance'. It was noted that these associations were significant even after the effect of age and sex were accounted for in a multivariate analysis.