The development and regulatory approval of immunomodulatory pharmaceuticals to treat many human diseases has increased significantly over the last two decades. As discussed by FDA and ICH guidelines, all human pharmaceuticals in... more
The development and regulatory approval of immunomodulatory pharmaceuticals to treat many human diseases has increased significantly over the last two decades. As discussed by FDA and ICH guidelines, all human pharmaceuticals in development should be evaluated for potential adverse effects on the immune system. Developmental immunotoxicology (DIT) focuses on the concern that early-life (during pre-/post-natal development) exposure to agents which target the immune system may result in enhanced susceptibility to immune-related disease (e.g., infection, autoimmunity, and cancer, particularly leukemia) compared to adults, unique effects not observed in adults, or more persistent effects in comparison to those following adult exposure. This article provides a substantive review of the literature and presents detailed considerations for DIT testing strategies with a specific focus on pharmaceuticals and biopharmaceuticals. In this regard, differences between small molecule and large molecule therapeutics will be considered, along with recommendations for best practices in the assessment of DIT during drug development. In addition, gaps in the DIT knowledge base and current testing strategies are identified. Finally, a summary of an ILSI-HESI-ITC sponsored Workshop conducted in 2010, entitled 'Developmental Immunotoxicity Testing of Pharmaceuticals' will be presented. This Workshop consisted of participants from the pharmaceutical, biotechnology, academic, and regulatory sectors, where many of the issues relating to DIT outlined in this review were discussed, key points of consensus reached, and current gaps in the science identified.
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Research Interests: Animal Studies, Clinical Trial, Toxicology, Biotechnology, Biology, and 15 moreMedicine, Transgenic Mice, Mice, Animals, Laboratory Animals, Proteins, Immune system, Antibody, Macaca Mulatta, Toxicity Tests, PRECLINICAL, Recombinant Proteins, Immunogenicity, Drug hypersensitivity, and Pharmacology and pharmaceutical sciences
Research Interests: Biology, Pharmacokinetics, Medicine, Antibodies, Toxicity, and 14 moreAnimals, Immunization, Analog, Antibody, Rhesus Monkey, Macaca Mulatta, Tissue Plasminogen Activator, Recombinant Proteins, Enzymatic Activity, Immunogenicity, Mono, Plasminogen Activator, Antibody Response, and Pharmacology and pharmaceutical sciences
The relative concentrations of antibodies produced in monkeys against three forms of human growth hormone (hGH) were determined using an antigen-specific avidin/biotin ELISA assay. Monkeys were treated in two separate 90-day studies with... more
The relative concentrations of antibodies produced in monkeys against three forms of human growth hormone (hGH) were determined using an antigen-specific avidin/biotin ELISA assay. Monkeys were treated in two separate 90-day studies with recombinant methionyl-hGH (met-hGH) and pituitary-derived hGH (pit-hGH) (Study 1) and recombinant natural sequence hGH (Study 2). The lowest dose was equal to the expected therapeutic dose of 0.1 IU/kg. Sixty-nine percent of monkeys treated with pit-hGH and 81% of those treated with met-hGH developed detectable anti-hGH responses. The magnitudes of the responses exhibited wide animal to animal variability, were not markedly related to dose or sex, and were lower than levels obtained in monkeys immunized with hGH in Freund's adjuvant. In contrast, the incidence of antibody responses in monkeys treated with natural sequence hGH was lower (23% in one experiment and 5% in a replicate experiment) and took longer to develop. Antibody concentrations were lower, on average, than in those animals treated with met- or pit-hGH. These results are in accord with those observed clinically, thus supporting the use of the monkey model to predict the relative immunogenicity of some proteins in humans.
Research Interests: Endocrinology, Biology, Medicine, Growth Hormone, Humans, and 13 moreInternal Medicine, Human Growth Hormone, Animals, Recombinant DNA, Antibody, Rhesus Monkey, Macaca Mulatta, Recombinant Proteins, Enzyme Linked Immunosorbent Assay, Immunogenicity, Anterior Pituitary, immunoglobulin G, and Pharmacology and pharmaceutical sciences
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Previous investigations from our laboratory have shown that the benzene metabolite, hydroquinone (HQ), inhibits B cell production by preventing the maturation of pre-B cells. Data presented in this paper demonstrate that HQ interrupts... more
Previous investigations from our laboratory have shown that the benzene metabolite, hydroquinone (HQ), inhibits B cell production by preventing the maturation of pre-B cells. Data presented in this paper demonstrate that HQ interrupts B-lymphopoiesis indirectly by inhibiting the production of interleukin-4 (IL-4) by fibroblastic stromal cells. HQ exposure of fibroblastic stromal cells (SCL-173 and SCL-160) did not affect IL-4 production by these cell lines at any dose tested. Addition of untreated bone marrow-derived macrophages to HQ-treated bone marrow stromal cells (heterogeneous population of fibroblastic cells and macrophages) reversed inhibition of IL-4 production. However, addition of HQ-treated macrophages was without effect. Our studies suggest that HQ inhibits macrophage production of IL-1, a potent inducer of IL-4 production by bone marrow fibroblastic stromal cells. Interruption of IL-1 release from macrophages mediates the observed inhibition of B lineage cell maturation.
Research Interests: Biology, Macrophages, Medicine, Hematopoiesis, Cell line, and 15 moreMice, Pubmed, Animals, Male, Bone marrow, Clinical Sciences, Lipopolysaccharides, Interleukins, B Lymphocytes, Cell communication, Interleukin, Lymphopoiesis, Cardiovascular medicine and haematology, Paediatrics and reproductive medicine, and Pharmacology and pharmaceutical sciences
From observations in rodents and, to a lesser extent, in humans inadvertently or occupationally exposed, it appears that a number of xenobiotics adversely affect immune homeostatic systems, either through acting as a hapten and resulting... more
From observations in rodents and, to a lesser extent, in humans inadvertently or occupationally exposed, it appears that a number of xenobiotics adversely affect immune homeostatic systems, either through acting as a hapten and resulting in hypersensitivity reactions or through altering hematopoietic or immune functions. At present, however, there is no evidence that the immune or hematopoietic systems of the general population have been compromised by xenobiotics via environmental exposure. Nonetheless, these examples and our current knowledge about the pathogenesis of disease support the possibility that chemical-induced damage to the immune system may be associated with potential pathological conditions, some of which may become detectable only after a long latency. Likewise, exposure to immunotoxic xenobiotics might represent additional risk to individuals with already fragile immune systems (e.g., in malnutrition, infancy, old age). However, it is important to be cautious when attempting to extrapolate meaningful conclusions from experimental data or isolated epidemiologic studies to risk assessment for low-level human exposure.
Research Interests: Hematology, Immunology, Medicine, Allergy, Humans, and 15 moreAnimals, Disease, Bone marrow, Clinical Sciences, Immune system, Occupational Exposure, Immune function, Environmental Pollutants, Immune Tolerance, Hypersensitivity, Epidemiologic Studies, Experimental Data, Environmental Exposure, General Population, and Human Exposure
Research Interests: Pathology, Physiology, Chemotherapy, Medicine, Bone marrow, and 4 moreHaematopoiesis, Unknown, Organs, and Strains
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ABSTRACT With repeated administration to animals, the cationic, amphiphilic drug, cnlorphentermine (CP), has been shown by others to induce a phospholipidosis in lymphocytes. In the present study mouse splenic lymphocytes, exposed to CP,... more
ABSTRACT With repeated administration to animals, the cationic, amphiphilic drug, cnlorphentermine (CP), has been shown by others to induce a phospholipidosis in lymphocytes. In the present study mouse splenic lymphocytes, exposed to CP, either in vivo or in vitro, developed morphological changes consistant With the induction of phospholipidosis. In addition, CP induced functional changes in lymphocytes. Mice, treated with CP in vivo, demonstrated a significantly depressed ability to generate a delayed hypersensitivity response or to produce antibody-secreting cells against de novo antigens. Mouse splenic lymphocytes, exposed to 10−7 M CP for 3 days in vitro, demonstrated a signficantly depressed blastogenic response to the mitogens phytohemagglutinin, concanavalin A and lipopolysaccharide. CP inhibited an event that occurred early during lymphocyte activation, but was subsequent to mitogen/receptor coupling. In addition, CP significantly depressed the increased uptake of choline that occurs in lymphocytes following cellular activation. Since the presence of phospholipidosis is indicative of an impairment in phospho lipid metabolism, these results taken together provide evidence for a relationship between this phenomenon and a ltered immune function.
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Cyclophosphamide severely inhibits the function of various hemic precursor cells in mice. In these studies we compared the effects of Cy on early B-lymphocytic precursor cells in mouse bone marrow to those effects on bone marrow myeloid... more
Cyclophosphamide severely inhibits the function of various hemic precursor cells in mice. In these studies we compared the effects of Cy on early B-lymphocytic precursor cells in mouse bone marrow to those effects on bone marrow myeloid precursor cells and splenic lymphoid precursor cells. These studies demonstrated that: 1) Pre-ARC in the bone marrow were extremely sensitive to even low doses of Cy (50 mg/kg) with virtually no renewal of this precursor population 11 days after injection of 200 mg/kg. 2) The sensitivity of pre-ARC to Cy along with the lack of their renewal was exemplified by the virtual absence of functional ARC in the spleen when assessed 11 days after injection of 200 mg/kg of Cy. 3) A rapid multiphasic renewal pattern was observed for myelocytic progenitor cells. 4) In general, LPS responsive cells were suppressed to a greater extent than were Con A responsive cells, especially with lower doses of Cy.
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Age-related decreases in humoral immune function have been well documented. In aged mice, these functional deficits may be due, in part, to decreased numbers of precursor B cells. Interleukin-7 (IL-7) plays a key role in B cell... more
Age-related decreases in humoral immune function have been well documented. In aged mice, these functional deficits may be due, in part, to decreased numbers of precursor B cells. Interleukin-7 (IL-7) plays a key role in B cell development by stimulating proliferation of progenitor and pre-B cells. In the current study, proliferation of the murine IL-7-dependent pre-B cell line SCID/FC-7 (SCID) was used to assess IL-7 activity in long-term bone marrow culture-conditioned medium (LTBMC-CM) from both young (4-8-week-old) and older (16-40-week-old) mice. Time to reach peak production and peak IL-7 levels were similar in both groups and was optimal between weeks 2 and 6 of culture. IL-7 activity in LTBMC-CM from older mice fell rapidly to negligible levels after 8 weeks in culture. These findings are consistent with age-related changes in stem cell production and B lymphopoiesis in LTBMC reported in other studies.
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Exposure to benzene has long been associated with myelotoxicity. A variety of blood dyscrasias attributed to benzene exposure has been reported including leukopenia, pancytopenia, bone marrow hypoplasia or aplasia, thrombocytopenia,... more
Exposure to benzene has long been associated with myelotoxicity. A variety of blood dyscrasias attributed to benzene exposure has been reported including leukopenia, pancytopenia, bone marrow hypoplasia or aplasia, thrombocytopenia, granulocytopenia and lymphocytopenia (Aksoy et al, 1971; 1972 Goldwater, 1941; for review see Laskin & Goldstein, 1977). Among these abnormalities one of the most frequently cited is lymphocytopenia. In one of the few controlled studies of workers exposed to benzene, Goldwater reported the frequent occurrence of an absolute lymphocytopenia in affected individuals (1941), and additional studies have reported a correlation between lymphocytopenia and altered immunologic parameters in workers exposed to benzene (Lange et al, 1973a,b; Revnova, 1962; Roth et al, 1972). Lymphocytopenia results from benzene exposure in experimental animals as well. Several studies have demonstrated that benzene exposure in rats or rabbits result in bone marrow hypoplasia accompanied by a dose-related lymphocytopenia which precedes a decrease in the number of other circulating cells (Selling, 1916; Weiskotten et al, 1920; Svirbely et al, 1944; Nau et al, 1966; Irons et al, 1979; Irons & Moore, 1980; Irons, 1980).
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Bioactivation of diaziquone (AZQ) in HT-29 human colon carcinoma cells and detoxification of benzene metabolites in bone marrow stromal cells were used as examples of the potential role of DT-diaphorase in both activation and deactivation... more
Bioactivation of diaziquone (AZQ) in HT-29 human colon carcinoma cells and detoxification of benzene metabolites in bone marrow stromal cells were used as examples of the potential role of DT-diaphorase in both activation and deactivation processes. HT-29 cell cytosol contained high levels of DT-diaphorase activity and removed AZQ in the presence of either NADH or NADPH. Prior boiling of cytosol, omission of NADH or NADPH or inclusion of dicoumarol, an inhibitor of DT-diaphorase, inhibited removal of AZQ. AZQ-induced cytotoxicity in HT-29 cells was also inhibited by dicoumarol. Chemical reduction of AZQ in a cell free system enhanced formation of a GSH conjugate of AZQ. Two of the major cell types in bone marrow stroma are macrophages and fibroblastoid stromal cells. A fibroblastoid cell line derived from stromal cells contained approximately fourfold higher levels of DT-diaphorase than macrophages. Inclusion of dicoumarol in incubations containing 14C-hydroquinone and the respective stromal cell type, significantly increased covalent binding of radiolabel to macromolecules in stromal fibroblasts but not in macrophages.
Research Interests: Biochemistry, Chemistry, Macrophages, Free Radical, Biological Sciences, and 15 moreHumans, Animals, Male, Detoxification, Bone marrow, High Pressure Liquid Chromatography, CHEMICAL SCIENCES, Aziridines, Biotransformation, Benzene, Benzoquinones, Bone Marrow Cells, fibroblasts, Medical and Health Sciences, and Colonic Neoplasms
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ABBREVIATIONS: c, cytoplasmic heavy chain of 1gM; sIgM, surface immunoglobulin M; FBS-HI, heat-inactivated fetal bovine serum; HEPES,
Bone marrow stromal cells appear to be key regulatory elements in hematopoiesis and lymphopoiesis. These stromal cells respond to cytokine exposure and alter their pattern of hematopoietic growth factor production, suggesting a degree of... more
Bone marrow stromal cells appear to be key regulatory elements in hematopoiesis and lymphopoiesis. These stromal cells respond to cytokine exposure and alter their pattern of hematopoietic growth factor production, suggesting a degree of functional plasticity. We examined the effect of two cytokines, interleukin-1 (IL-1) and IL-4, on stromal cell regulation of pre-B cell generation using the bone marrow stromal cell line, S17. Neither lymphokine potentiated pre-B cell generation in the absence of stromal cells. However, addition of either 10 U/mL rIL-1 alpha or 50 U/mL rIL-4 to cultures of bone marrow cells containing S17 cells dramatically suppressed subsequent pre-B cell formation. Preculture of S17 stromal cells with either rIL-1 or rIL-4 completely abrogated their ability to support pre-B cell generation in subsequent coculture with freshly explanted bone marrow cells. Conditioned medium from IL-1- or IL-4-treated S17 cells also suppressed pre-B-cell generation in culture. Altho...
Research Interests: Biology, Cytokines, Cell Biology, Medicine, Hematopoiesis, and 15 moreHematopoietic Stem Cells, Animals, Blood, Male, Bone marrow, Haematopoiesis, Clinical Sciences, Cytokine, B Lymphocytes, Biological Factors, Bone Marrow Cells, Interleukin, Lymphopoiesis, Cardiovascular medicine and haematology, and In Vitro Techniques
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1Center for Biologics Evaluation and Research; 2Biogen, Inc.; 3Covance Laboratories; 4Access BIO; 5Novo Nordisk A/S Agency; 6lmmunex, Inc.; 7Genetics Institute; 8National Institute of Health Sciences, Japan; 9Sierra Biomedical, Inc.; 1... more
1Center for Biologics Evaluation and Research; 2Biogen, Inc.; 3Covance Laboratories; 4Access BIO; 5Novo Nordisk A/S Agency; 6lmmunex, Inc.; 7Genetics Institute; 8National Institute of Health Sciences, Japan; 9Sierra Biomedical, Inc.; 1 SmithKline Beecham;"Center for Drug Education and Research; '2Wyeth Ayerst Research; '3Medical Products Agency, Sweden; "'CentoCor, Inc.; 5Lilly Research Laboratories
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Bioactivation of diaziquone (AZQ) in HT-29 human colon carcinoma cells and detoxification of benzene metabolites in bone marrow stromal cells were used as examples of the potential role of DT-diaphorase in both activation and deactivation... more
Bioactivation of diaziquone (AZQ) in HT-29 human colon carcinoma cells and detoxification of benzene metabolites in bone marrow stromal cells were used as examples of the potential role of DT-diaphorase in both activation and deactivation processes. HT-29 cell cytosol contained high levels of DT-diaphorase activity and removed AZQ in the presence of either NADH or NADPH. Prior boiling of cytosol, omission of NADH or NADPH or inclusion of dicoumarol, an inhibitor of DT-diaphorase, inhibited removal of AZQ. AZQ-induced cytotoxicity in HT-29 cells was also inhibited by dicoumarol. Chemical reduction of AZQ in a cell free system enhanced formation of a GSH conjugate of AZQ. Two of the major cell types in bone marrow stroma are macrophages and fibroblastoid stromal cells. A fibroblastoid cell line derived from stromal cells contained approximately fourfold higher levels of DT-diaphorase than macrophages. Inclusion of dicoumarol in incubations containing 14C-hydroquinone and the respective stromal cell type, significantly increased covalent binding of radiolabel to macromolecules in stromal fibroblasts but not in macrophages.
Research Interests: Biochemistry, Chemistry, Macrophages, Free Radical, Biological Sciences, and 15 moreHumans, Animals, Male, Detoxification, Bone marrow, High Pressure Liquid Chromatography, CHEMICAL SCIENCES, Aziridines, Biotransformation, Benzene, Benzoquinones, Bone Marrow Cells, fibroblasts, Medical and Health Sciences, and Colonic Neoplasms
Environmental exposure to benzene results in both myelotoxicity and immunotoxicity. Although benzene-induced immunotoxicity has been well documented, no studies to date have addressed the possibility that benzene toxicity is due in part... more
Environmental exposure to benzene results in both myelotoxicity and immunotoxicity. Although benzene-induced immunotoxicity has been well documented, no studies to date have addressed the possibility that benzene toxicity is due in part to altered differentiation of marrow lymphoid cells. We investigated the effect of acute exposure to the benzene metabolite, hydroquinone, on murine bone marrow B-lymphopoiesis. Bone marrow cell suspensions from B6C3F1 (C57BL/6J x C3H/HeJ) mice were depleted of mature surface IgM+ (sIgM+) B cells and cultured for 0, 24, 48, or 72 hr and production of newly formed B cells was assayed both by sIgM expression and colony formation in soft agar cultures. One hr exposure of bone marrow cells to hydroquinone before culture reduced the number of sIgM+ cells generated in liquid cultures. Small pre-B cells (cytoplasmic mu heavy chain+, sIgM-) were numerically elevated as compared with control cultures. Hydroquinone exposure also decreased the number of adheren...
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... Koren E, De Groot AS, Jawa V, Beck KD, Boone T, Rivera D, Li L, Mytych D, Koscec M, Weeraratne D, Swanson S, Martin W ... Loisel S, Ohresser M, Pallardy M, Dayd'e D, Berthou C, Cartron G, Watier H. Relevance, advantages and... more
... Koren E, De Groot AS, Jawa V, Beck KD, Boone T, Rivera D, Li L, Mytych D, Koscec M, Weeraratne D, Swanson S, Martin W ... Loisel S, Ohresser M, Pallardy M, Dayd'e D, Berthou C, Cartron G, Watier H. Relevance, advantages and limitations of animal models used in the ...
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The potential immunotoxicity of tabalumab was assessed as a component of standard pre-clinical toxicology studies in cynomolgus monkeys. To evaluate potential tabalumab-associated immunosuppression after antigen challenge, cynomolgus... more
The potential immunotoxicity of tabalumab was assessed as a component of standard pre-clinical toxicology studies in cynomolgus monkeys. To evaluate potential tabalumab-associated immunosuppression after antigen challenge, cynomolgus monkeys were administered placebo control or tabalumab in three immunotoxicological safety studies. Study 1, a 4-week pilot study, evaluated biweekly intravenous (IV) control, and 0.3, 1.0, 5.0, and 15.0 mg/kg tabalumab doses. Study 2 evaluated IV control, and 0.1, 1.0, and 30.0 mg/kg tabalumab doses biweekly for 6 weeks. Study 3 evaluated IV control and 0.1, 1.0, 30.0 mg/kg, and subcutaneous (SC) 30.0 mg/kg tabalumab biweekly for 6 months, with recovery (16 weeks) to monitor standard immunotoxicity endpoints. T-cell dependent primary and secondary antibody responses to tetanus toxoid antigen challenge (4-week and 6-week studies) or keyhole limpet hemocyanin (KLH; 6-week and 6-month studies) were evaluated as a measure of immunocompetence, together with...
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Hydroquinone and catechol are two metabolites of benzene that are potential inducers of hematotoxicity. We investigated the in vivo toxicity of these metabolites toward the development of polyclonal, plaque-forming cells (PC-PFC) from... more
Hydroquinone and catechol are two metabolites of benzene that are potential inducers of hematotoxicity. We investigated the in vivo toxicity of these metabolites toward the development of polyclonal, plaque-forming cells (PC-PFC) from progenitor B lymphocytes. Dextran sulfate (DxS), lipopolysaccharide (LPS), or the two mitogens combined (DxS + LPS) were used to induce proliferation and maturation of these progenitors to PC-PFC. Groups of 4 C57BL/6 mice were exposed to 2 daily doses, either intravenously or intraperitoneally, of hydroquinone (100 mg/kg) or catechol (75 mg/kg) for 3 consecutive days. Spleen and marrow cells were harvested for culture 1 day later. The results demonstrated that both metabolites were cytotoxic to spleen cells. Hydroquinone (100 mg/kg) also reduced marrow cellularity, whereas catechol (75 mg/kg) did not significantly affect marrow cellularity. Each compound reduced the frequency of PC-PFC developed from the spleens and marrows of treated mice, but only ca...
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Four platinum compounds, cis-dichlorodiammineplatinum, dichloro- 1,2-benzenediamine-N,N'-platinum, cis-dichlorobis-(cyclohexylamine)platinum and cis-dichlorobis(cyclopentylamine)platinum, were studied for their toxicity toward... more
Four platinum compounds, cis-dichlorodiammineplatinum, dichloro- 1,2-benzenediamine-N,N'-platinum, cis-dichlorobis-(cyclohexylamine)platinum and cis-dichlorobis(cyclopentylamine)platinum, were studied for their toxicity toward myelocytic progenitor cells (CFC assay) and pre-antigen reactive cells (P-PFC assay) in murine bone marrow and toward antigen reactive cells in the mouse spleen (MD-PFC assay). It was demonstrated that each of the platinum compounds markedly suppressed the ability of splenic antigen reactive cells to generate antibody producing cells (MD-PFC) 3 days after i.v. injection. At the same time, certain doses of each of the platinum compounds induced selective recovery of the preantigen reactive cells (P-PFC) and myelocytic progenitor cells (CFC) in the bone marrow with a pattern that was unique for each compound. It was also demonstrated with cis-dichlorodiammineplatinum that the recovery for both bone marrow precursor cell populations was multiphasic with time....
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Research Interests: Spleen, Serology, Mice, Female, Animals, and 5 moreCisplatin, T lymphocytes, Lipopolysaccharides, Time Factors, and B Lymphocytes
The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both... more
The number of anti-inflammatory and immunomodulatory drugs being developed in the pharmaceutical industry has increased considerably in the past decade. This increase in research and development has been paralleled by questions from both regulatory agencies and industry on how best to assess decreased host resistance to infections or adverse immunostimulation caused by immunomodulatory agents such as anti-cytokine antibodies (e.g., the tumor necrosis factor-alpha inhibitors), anti-adhesion molecule antibodies (e.g., anti-alpha-4 integrin inhibitors) and immunostimulatory molecules (e.g., anti-CD28 antibodies). Although several methods have been developed for nonclinical assessment of immunotoxicity, highly publicized adverse events have brought to light significant gaps in the application of nonclinical immunotoxicity testing in assessing potential risk in humans. Confounding this problem is inconsistent application of immunotoxicology methods for risk assessment within the scientific community, limited understanding of appropriate immunotoxicity testing strategy for immunomodulators and inconsistent testing requests by regulatory agencies. To address these concerns, The Immunotoxicology Technical Committee (ITC) of the International Life Science Institute (ILSI) Health and Environmental Sciences Institute (HESI) organized a workshop on Immunomodulators and Clinical Immunotoxicology in May 2007. The Workshop was convened to identify key gaps in nonclinical and clinical immunotoxicity testing of anti-inflammatory and immunomodulatory agents and to begin to develop consistent approaches for immunotoxicity testing and risk assessment. This paper summarizes the outcome of the HESI ITC Immunomodulators and Clinical Immunotoxicology Workshop. Topics not discussed at the Workshop were outside the scope of this report. Although more work is needed to develop consistent approaches for immunotoxicity assessment of immunomodulators, this Workshop provided the foundation for future discussion.
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Research Interests: Hematopoiesis, Hematopoietic Stem Cells, Mice, Animals, Male, and 7 moreQuinones, Bone marrow, Phenol, Phenols, Catechols, Benzene, and Benzoquinones
After cessation of cisplatin (cis-dichlorodiammineplatinum) chemotherapy, selective recovery of certain cell lineages occurs during bone marrow hemopoiesis. To further investigate the process of selective hemopoiesis, we combined the use... more
After cessation of cisplatin (cis-dichlorodiammineplatinum) chemotherapy, selective recovery of certain cell lineages occurs during bone marrow hemopoiesis. To further investigate the process of selective hemopoiesis, we combined the use of buoyant density gradient separation, morphology, and lymphocyte function assays to characterize changes in the hemopoiesis of immature and mature marrow cells after exposure to cisplatin. A single, cytotoxic dose of cisplatin was administered to B6D2F1 male mice, and marrow cell suspensions were taken from these mice 3 and 7 days later to characterize hemopoietic recovery. Morphology and buoyant density separation of marrow cells revealed that the most significant changes in cellular composition occurred at Day 3. At this time, there was an increase in immature white blood cells (WBCs) and immature polymorphoneutrophils (PMNs) with a concomitant reduction in immature red blood cells (RBCs). By Day 7, the normal proportion of immature RBCs, immature WBCs, and PMNs was restored; however, the buoyant distribution patterns for PMNs indicated that a greater proportion of immature PMNs was still present relative to marrow suspensions from normal mice. Fewer lymphocytes were also observed in marrows from the Day 7 group when compared with controls. Lymphocyte function tests indicated reduced mitogen responsiveness of lymphocytes from both Day 3 and Day 7; however, more immature lymphocytes were present after 7 days than were seen with either normal or Day 3 marrow suspensions. Overall, the results indicated that hemopoiesis proceeded through a specific hierarchy which began with the restoration of the erythrocyte line followed by the leukocyte cell lines. Lymphocyte recovery lagged behind the restoration of all the cell lineages examined.
Research Interests: Cell separation, Hematopoiesis, Mice, Animals, Male, and 5 moreBone marrow, Cisplatin, Neutrophils, Lymphocytes, and Erythrocytes
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Age-related decreases in humoral immune function have been well documented. In aged mice, these functional deficits may be due, in part, to decreased numbers of precursor B cells. Interleukin-7 (IL-7) plays a key role in B cell... more
Age-related decreases in humoral immune function have been well documented. In aged mice, these functional deficits may be due, in part, to decreased numbers of precursor B cells. Interleukin-7 (IL-7) plays a key role in B cell development by stimulating proliferation of progenitor and pre-B cells. In the current study, proliferation of the murine IL-7-dependent pre-B cell line SCID/FC-7 (SCID) was used to assess IL-7 activity in long-term bone marrow culture-conditioned medium (LTBMC-CM) from both young (4-8-week-old) and older (16-40-week-old) mice. Time to reach peak production and peak IL-7 levels were similar in both groups and was optimal between weeks 2 and 6 of culture. IL-7 activity in LTBMC-CM from older mice fell rapidly to negligible levels after 8 weeks in culture. These findings are consistent with age-related changes in stem cell production and B lymphopoiesis in LTBMC reported in other studies.
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The assessment of the immunogenicity of recombinant therapeutic proteins (RTPs) has received more attention in the past 4 years than in the previous 20 years. The induction of clinically adverse events in RTP-treated patients and the... more
The assessment of the immunogenicity of recombinant therapeutic proteins (RTPs) has received more attention in the past 4 years than in the previous 20 years. The induction of clinically adverse events in RTP-treated patients and the subsequent measurement of antibodies to those RTPs has challenged the scientific community to re evaluate the methods and techniques used for determining the immunogenic potential of therapeutic proteins. One preclinical strategy for determining the relative immunogenicity of RTPs is the use of a comparative hyperimmunization technique in animals that optimizes an immunological response. This approach has utility for analyzing the immunogenic potential of different formulations as well as for potential adverse effects. The hyperimmunization model may also provide a source of antisera specific to the RTP that can be used during selection of the appropriate assay technique(s) and conditions for measuring the immune response. Solid- or liquid-phase, affini...
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Cyclophosphamide severely inhibits the function of various hemic precursor cells in mice. In these studies we compared the effects of Cy on early B-lymphocytic precursor cells in mouse bone marrow to those effects on bone marrow myeloid... more
Cyclophosphamide severely inhibits the function of various hemic precursor cells in mice. In these studies we compared the effects of Cy on early B-lymphocytic precursor cells in mouse bone marrow to those effects on bone marrow myeloid precursor cells and splenic lymphoid precursor cells. These studies demonstrated that: 1) Pre-ARC in the bone marrow were extremely sensitive to even low doses of Cy (50 mg/kg) with virtually no renewal of this precursor population 11 days after injection of 200 mg/kg. 2) The sensitivity of pre-ARC to Cy along with the lack of their renewal was exemplified by the virtual absence of functional ARC in the spleen when assessed 11 days after injection of 200 mg/kg of Cy. 3) A rapid multiphasic renewal pattern was observed for myelocytic progenitor cells. 4) In general, LPS responsive cells were suppressed to a greater extent than were Con A responsive cells, especially with lower doses of Cy.