MDS disease characteristics, not donor source, predict hematopoietic stem cell transplant outcomes.

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematological malignancies with considerably variable prognoses and curable only with hematopoietic cell transplantation (HCT). Few studies comparing MDS HCT outcomes between sibling and umbilical cord blood (UCB) donors exist. Using the University of Minnesota Blood and Marrow Transplant (BMT) database, we retrospectively analyzed HCT outcomes among 89 MDS patients undergoing either sibling or double UCB HCT in 2000-2013. We observed similar survival, relapse and non-relapse mortality between sibling and UCB donor sources. Relapse was increased in those with monosomal karyotype (P=0.04) and with reduced intensity conditioning (P<0.01). In summary, our data highlight similar MDS HCT outcomes regardless of donor source and support the use of UCB as an alternative donor when a sibling is unavailable.

Novel disease burden assessment predicts allogeneic transplantation outcomes in myelodysplastic syndrome.

Among patients with myelodysplastic syndrome (MDS) undergoing hematopoietic cell transplantation (HCT), the impact of residual pretransplant cytogenetically abnormal cells on outcomes remains uncertain. We analyzed HCT outcomes by time of transplant disease variables, including (1) blast percentage, (2) percentage of cytogenetically abnormal cells and (3) Revised International Prognostic Scoring System (R-IPSS) cytogenetic classification. We included 82 MDS patients (median age 51 years (range 18-71)) transplanted between 1995 and 2013 with abnormal diagnostic cytogenetics. Patients with higher percentages of cytogenetically abnormal cells experienced inferior 5-year survival (37-76% abnormal cells: relative risk (RR) 2.9; 95% confidence interval (CI) 1.2-7.2; P=0.02; and 77-100% abnormal cells: RR 5.6; 95% CI 1.9-19.6; P<0.01). Patients with >10% blasts also had inferior 5-year survival (RR 2.9; 95% CI 1.1-7.2; P=0.02) versus patients with ⩽2% blasts. Even among patients with ⩽2% blasts, patients with 77-100% cytogenetically abnormal cells had poor survival (RR 4.4; 95% CI 1.1-18.3; P=0.04). Increased non-relapse mortality (NRM) was observed with both increasing blast percentages (P<0.01) and cytogenetically abnormal cells at transplant (P=0.01) in multivariate analysis. We observed no impact of disease burden characteristics on relapse outcomes due to high 1-year NRM. In conclusion, both blast percentage and percentage of cytogenetically abnormal cells reflect MDS disease burden and predict post-HCT outcomes.

Hemorrhagic cystitis after allogeneic hematopoietic cell transplantation: risk factors, graft source and survival.

Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well known. We evaluated HC in a large cohort (n=1321, 2003-2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute GVHD, fever, severe thrombocytopenia and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III-IV) was associated with increased treatment-related mortality but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis, and early interventions to limit its severity are still needed.

Design and implementation of a randomized crossover study of valproic acid and antiretroviral therapy to reduce the HIV reservoir.

BACKGROUND: HIV reservoirs represent the major obstacles for eradication and are defined as a cell type that allows persistence of replication-competent HIV in patients on optimal long-term antiretroviral therapy (HAART). Several pilot clinical trials have been implemented to assess the value of experimental therapy to reduce reservoir size or eradicate HIV. In order to eradicate HIV, valproic acid was used as a new strategy to increase viral gene expression in the nucleus of infected cells with the expectation of generating a direct cell death or destruction by nearby cytotoxic cells. Previous pilot studies using VPA have showed conflicting results on the ability of VPA to reduce the size of HIV reservoirs. PURPOSE: As the role of VPA on HIV reservoirs remains unclear, we conducted a multicenter clinical trial with a specific study design to obtain optimal information on reservoir changes while exposing the smallest number of individuals to the experimental medication. METHOD: To this aim, a randomized, crossover design with 2 different treatment durations was implemented. By doubling the therapeutic period in one study arm, we were in a position to assess the impact of an extended duration of VPA on the size of the HIV reservoir and to evaluate the duration of treatment effects upon VPA withdrawal in the other arm. However, limitations for this type of study design included the logistical complexity of 2 uneven study arms and longer study duration. CONCLUSION: Despite the absence of demonstrable impact of VPA on reservoir size, such crossover study design should be considered in the early stage testing of novel HIV therapeutics targeted to reduce reservoir size or eradicate HIV.

Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study.

OBJECTIVES: Conflicting results have been reported regarding the ability of valproic acid (VPA) to reduce the size of HIV reservoirs in patients receiving suppressive highly active antiretroviral therapy (HAART). In a randomized multicentre, cross-over study, we assessed whether adding VPA to stable HAART could potentially reduce the size of the latent viral reservoir in CD4 T cells of chronically infected patients. METHODS: A total of 56 virologically suppressed patients were randomly assigned either to receive VPA plus HAART for 16 weeks followed by HAART alone for 32 weeks (arm 1; n = 27) or to receive HAART alone for 16 weeks and then VPA plus HAART for 32 weeks (arm 2; n = 29). VPA was administered at a dose of 500 mg twice a day (bid) and was adjusted to the therapeutic range. A quantitative culture assay was used to assess HIV reservoirs in CD4 T cells at baseline and at weeks 16 and 48. RESULTS: No significant reductions in the frequency of CD4 T cells harbouring replication-competent HIV after 16 and 32 weeks of VPA therapy were observed. In arm 1, median (range) values of IU per log(10) billion (IUPB) cells were 2.55 (range 1.20-4.20), 1.80 (range 1.0-4.70) and 2.70 (range 1.0-3.90; P = 0.87) for baseline, week 16 and week 48, respectively. In arm 2, median values of IUPB were 2.55 (range 1.20-4.65), 1.64 (range 1.0-3.94) and 2.51 (range 1.0-4.48; P = 0.50) for baseline, week 16 and week 48, respectively. CONCLUSIONS: Our study demonstrates that adding VPA to stable HAART does not reduce the latent HIV reservoir in virally suppressed patients.

Treatment durability, effectiveness, and safety with atazanavir/ritonavir-based HAART regimen in treatment-naïve HIV-infected patients.

PURPOSE: To describe the durability of treatment, virological and immunological response, and safety of an atazanavir/ritonavir (ATV/RTV)-based highly active antiretroviral therapy (HAART) regimen in treatment-naïve HIV-infected patients. METHODS: This was a multicentre retrospective study. Medical charts of antiretroviral-na'i've HIV-infected adults who initiated ATV/RTV (300/100 mg) from January 2004 to December 2007 in 10 Canadian clinics were reviewed. Data were collected from time of ATV/RTV treatment initiation until discontinuation of ATV. Durability of treatment and time to virological response were estimated with Kaplan-Meier functions. Change in viral load, CD4 cell counts, and lipid parameters were assessed with linear regression analyses. RESULTS: 176 patients were enrolled, 153 (86.9%) were male, and the majority (52.3%) were 40 to 54 years old. Duration of observation ranged from 1.6 to 56 months. The mean (SE) durability of treatment was 33.5 (0.7) months. There were 37 (21.0%) patients who discontinued ATV/ RTV, among whom 18 (10.2%) discontinued due to toxicity, suboptimal virological response, loss to follow-up, or death. The mean (SE) time to HIV viral load of <50 and <400 copies/mL was 6.6 (0.4) and 4.3 (0.3) months, respectively. At 96 weeks of treatment, least squares mean (LSM) estimated change in log10(HIV copies/mL) was -2.94 (P < .001) and +245 cells/mL (P < .001) for CD4 cell count. A significant LSM increase in HDL-C of 0.24 mmol/L (P = .007 for trend over time) was also observed; total cholesterol, triglycerides, and LDL-C increased over time but their change did not reach statistical significance. The most frequently reported adverse event was increased bilirubin (16.5%). CONCLUSIONS: ATV/RTV-based first-line HAART regimen demonstrated durability and effectiveness and was well tolerated in treatment-naïve HIV-infected patients.

Effect of antiretroviral therapy on HIV-1 genetic evolution during acute infection.

The rapid evolution of HIV-1 is a major obstacle to viral eradication. Early antiretroviral therapy (ART) during primary HIV-1 infection could limit viral diversity. Eighteen patients recently infected with HIV-1 were selected. Nine initiated ART soon after enrolment and nine remained untreated. Replication-competent (RC) viruses were quantified at baseline and after one year of follow-up. Viral diversity in the C2V5 envelope region was evaluated from plasma, peripheral blood mononuclear cells (PBMCs), and cell culture at both time points. The amount of RC virus in the treated group declined (median -5.42 infectious units per million [IUPM]) while it remained stable or increased in the untreated group (median +0.87 IUPM). At one year post infection, we observed a significant increase in diversity for the C2V5 (+0.150%) region, specifically in the hypervariable loops V4 (+0.73%) and V5 (+0.77%), in the untreated group. More importantly, viral diversity did not significantly increase in treated individuals during the first year post infection. Genetic diversity during primary infection remains low through the first year of infection. Early treatment could contribute to a decrease in RC viruses from PBMCs and to limitation of viral diversification in the viral reservoir. These findings may have relevance for the rational design of specific immunotherapeutic strategies.

Successful implementation of a national HLA-B*5701 genetic testing service in Canada.

Abacavir is a nucleoside reverse transcriptase inhibitor (NRTI) that is used in combination antiretroviral therapy in HIV-infected patients. It is currently recommended as a preferred or an alternative NRTI in antiretroviral-naïve patients. The major toxicity of abacavir is a hypersensitivity reaction (HSR), which occurs in approximately 5% of treated patients. There is a strong association between the human leukocyte antigen (HLA)-B*5701 allele and abacavir HSR, which has allowed for rapid acceptance of genetic screening for HLA-B*5701 in clinical use. Canadian clinicians working in hospital centers with HLA typing capacity opted to launch a pilot project in 2006 to offer the screening test as standard of care to HIV-infected patients. Currently, more than 11,000 HLA-B*5701 tests have been performed, among which 6.3% are positive. Continued efforts have been made to ensure that testing is available to all HIV-infected patients to widen the patients' therapeutic options. HLA-B*5701 screening shows clinical use and preliminary data suggest cost-effectiveness.

A large prospective study assessing injection site reactions, quality of life and preference in patients using the Biojector vs standard needles for enfuvirtide administration.

OBJECTIVES: To determine the severity of injection site reactions (ISRs), patient quality of life (QoL) and preference when enfuvirtide is administered by the Biojector (Bioject, Medical Technologies, Inc., Tualatin, OR, USA) relative to standard needles. METHODS: A total of 201 HIV-positive patients on stable enfuvirtide-based therapy (n=184) or initiating such therapy (n=17) were evaluated prospectively after switching from standard needles to the Biojector system. Patients used needles for a minimum of 2 weeks prior to switching to the Biojector. Questionnaires to assess the incidence and severity of ISRs (31-item score) and QoL [Medical Outcomes Study HIV Health Survey (MOS-HIV)] were administered at baseline and following a minimum of 14 days of Biojector use. RESULTS: The median changes in ISR score and number of ISRs following a median of 1.0 month [interquartile range (IQR) 0.9, 1.3] of Biojector use were -3 (IQR -7, 1) and -1 (IQR -3, 1), respectively. The severity of pain (P<0.0001), induration (P<0.0001), pruritus (P<0.0001), nodules (P<0.0001) and erythema (P<0.0001) all decreased with the Biojector. Administration of enfuvirtide with the Biojector was associated with an improved patient QoL (P<0.0001), and was preferred by 72% of patients. CONCLUSIONS: Compared with needles, the Biojector was associated with a decreased severity of ISRs and improved QoL in patients taking enfuvirtide.

Effects of drug resistance on viral load in patients failing antiretroviral therapy.

Previous studies on patients who develop drug resistant HIV-1 variants have shown that continued use of failing regimens might provide clinical benefit. However, the effect of long-term exposure to drug resistant variants may lead to emergence of compensatory mutations that may jeopardize this effect. In this study, we assess associations among type and number of drug resistant mutations, viral load and disease progression in patients with long-term follow up. Patients with genotypic testing performed at the time of treatment failure were enrolled. Comparison of viral load and CD4 cell count between different resistance groups was performed using analysis of variance. Multiple linear regression analysis was performed to assess the simultaneous effects of the presence of particular mutations and their accumulation on viral load. Data from 475 patients who were followed for a median of 43 months from October 1999 to July 2005 were studied. A "V shape" relationship was observed between the number of mutations and viral load. Specifically, in patients harboring up to five mutations, viral load was reduced by 0.8 log/copies when compared to wild-type variants. However, with more than six mutations viral load progressively increased. Certain reverse transcriptase mutations such as M184V/I, K70R, V108I, and protease mutations such as L33FIV, M84V, and M36I were associated with reduced viral load. Together, these findings suggest that long-term maintenance of a sub-optimal antiretroviral regimen may have deleterious consequences for the patient.

Immunotoxicological response of the earthworm Lumbricus terrestris following exposure to cement kiln dusts.

Cement kiln dusts are made of a complex mixture of elements. We have evaluated the potential negative impact of those dusts on the immune system of the earthworm Lumbricus terrestris. We specifically studied cell viability and phagocytic activity of coelomocytes extruded during electrical stimulation. We used two modes of exposures: in vitro, and soil incubation using OECD artificial soil media. Extruded coelomocytes were exposed 18 h in vitro to 10, 100, and 500 mg L(-1) of cement kiln dust particles. The phagocytosis and the cell viability were determined using a double-laser-flow acquisition cytometry system. Using the double laser allows us to use a dichlorofluorescein diacetate (DCFDA) marker to discriminate the biological cells from the cement kiln dusts. Dead cells are marked using propidium iodide (PI). All three exposure levels showed highly significant impacts on cell viability and phagocytic activity. The in vivo soil incubation was performed using 10, 100, and 1000 mg kg(-1) of cement kiln dusts incorporated into the OECD media. Here, to discriminate the biological cells from the mineral dusts we only needed to use PI. The day-to-day variability of the in vivo assay was high and although we can observe an overall reduction in cell viability at the highest concentration tested, no statistically significant effects could be observed on either cell viability or phagocytosis.

Immunotoxicity of aminocarb. III. Exposure route-dependent immunomodulation by aminocarb in mice.

Aminocarb, a phenylsubstituted methylcarbamate pesticide (4-dimethylamino-3-methyl-N-carbamate; matacil), previously suspected of a relatively low immunotoxic potential, was administered by four different exposure routes to C57BL/6 mice. A single sublethal exposure by oral and dermal routes stimulated humoral immune response at a relatively low dose; 1/256 LD50 of aminocarb. Intraperitoneal (i.p.) injection decreased the humoral PFC response, whereas inhalation of aminocarb had no marked effect on peripheral immune status in exposed animals. Thus, i.p. exposure resulted in higher immunotoxicity over oral administration of aminocarb. Similarly, marked route-related exposure differences in immunomodulatory effects of aminocarb were noted for mitogenic stimulation of spleen lymphocytes and mixed lymphocyte response. Other indices, such as delayed type hypersensitivity (DTH) and production of interleukin-2 (IL-2) were unchanged. Interestingly, expression of major histocompatibility complex (MHC) class II by purified, lipopolysaccharide (LPS)-stimulated B cells increased equally after i.p. and oral exposures to aminocarb. Overall, a weak immunosuppressive potential of aminocarb was concluded, which was possibly due to indirect interaction of the pesticide with the immune system. However, aminocarb may represent an autoimmunity-inducing toxic.

Studies on lipid peroxidation in rat tissues following administration of low and moderate doses of cadmium chloride.

The susceptibility to lipid peroxidation (LPO) of liver, kidneys, brains, lungs, heart, and testes was assessed in rats administered intraperitoneally with various doses of cadmium (Cd). Dose-response studies were carried out with male Long Evans rats (12-week-old; 300 +/- 33 g) injected with 25, 125, 500, and 1250 micrograms Cd/kg as CdCl2 and sacrificed after 24 h. In time-response studies, animals were administered with 25 and 500 micrograms Cd/kg as CdCl2 and sacrificed after 2, 6, 12, 24, and 72 h. Exposure of rats to low and moderate doses of Cd by the intraperitoneal route stimulated LPO in all the tissues investigated as assessed by the measurement of thiobarbituric acid reactive substances (TBARS). Lungs and brain were the most responsive, and these tissues and liver displayed early responses following Cd exposure. Comparison of LPO to various tissue indicators (for liver: alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), alkaline phosphatase (ALP); for lungs: ALP, gamma-glutamyl transpeptidase (GGT] suggested that low doses of Cd stimulated LPO without any evidence of acute damages. These results suggest that LPO is an early and sensitive consequence of Cd exposure as determined in various organs. Investigation of liver, lungs, and heart antioxidant defense system components (glutathione peroxidase (GPX), glutathione reductase (GR), glucose-6-phosphate dehydrogenase (G6PDH), superoxide dismutase (SOD] revealed that GPX might be considered as a potential modulator of the Cd-induced LPO reaction in lungs and heart tissues.

The response of the pulmonary surfactant-associated alkaline phosphatase following acute cadmium chloride inhalation.

In order to identify sensitive and specific biochemical indicators of pulmonary damages caused by industrial contaminants, male Long-Evans rats were exposed to a cadmium chloride (CdCl2) aerosol (5 mg Cd/m3; MMAD = 1.4 microns; SDg = 1.8) for 1 hr. The rats were sacrificed at 1, 4, 8, and 16 days after treatment. The response of the pulmonary surfactant (SF) system, which prevents alveolar collapse during expiration by lowering the surface tension at the air-liquid interface, was of particular interest. The effect of CdCl2 inhalation on the SF system was monitored by assaying the alkaline phosphatase (AKP) activity and phospholipid (PL) content in an enriched surface active SF fraction purified from bronchoalveolar lavages. The AKP activity of the SF fraction was markedly decreased (99%) on Day 1, indicating an inhibition of AKP by Cd. The PL content remained at control level while the total protein content was significantly increased (199%). On day 4, the high recovery of PL (207%) and AKP activities (639%) may reflect an increased secretion caused by Type II cell hyperplasia. By Day 8 these parameters returned to baseline levels. On Day 16 both the AKP activity and the PL content of the SF fraction were decreased significantly. Concurrently, the activities of the acid phosphatase and the B-N-acetylglucosaminidase followed, but to a lesser extent, the response of the AKP activity on Days 1 and 4. They differed from AKP, however, in that their activities remained significantly elevated on Day 8 and in that they returned to baseline levels on Day 16.(ABSTRACT TRUNCATED AT 250 WORDS)

Virus-pesticide interactions with murine cellular immunity after sublethal exposure to dieldrin and aminocarb.

Interaction of two potential immunosuppressive factors, sublethal pesticide exposure and viral inhibition of lymphocyte mitogenesis, was examined in mixed lymphocyte reaction (MLR). Inbred (C57Bl/6 x A/J)F mice, semisusceptible to mouse hepatitis virus 3 (MHV3) infection were exposed to selected pesticides and subsequently infected with the MHV3 virus. The mortality of animals was examined as a function of pesticide exposure. Two pesticides were selected for further studies: the organochlorine pesticide dieldrin, which increased the cumulative mortality of animals, and the carbamate pesticide aminocarb, which did not affect the virus-induced cumulative mortality of animals. Spleen lymphocytes from dieldrin- and aminocarb-exposed C57Bl/6 mice (susceptible to MHV3 infection) were used as responder cells in one-way MLR. A marked immunosuppression of the MLR proliferative response was observed in the dieldrin group, whereas sublethal exposure to aminocarb did not affect the in vitro MLR response. The MLR cultures were subsequently infected in vitro with the MHV3 virus, which resulted in a time-dependent and virus dose-dependent inhibition of lymphocyte proliferation. However, no synergism was observed with the addition of either the MHV3 virus-induced inhibition of in vitro MLR lymphoproliferative response or dieldrin-related immunosuppression, since in vitro MHV3 infection of cells from dieldrin-exposed mice did not aggravate the dieldrin-related immunosuppression. In addition, no "hidden" aminocarb-related damage of the lymphoproliferative response was noted, as the kinetics of the virus-induced inhibition in the aminocarb group were analogous to the control. In conclusion, dieldrin-induced immunosuppression of the cellular immune response, rather than MHV3 virus-induced inhibition of lymphoproliferative activity itself, was the primary factor potentially responsible for the impaired cellular response. Furthermore, the data support the observation that cell-mediated immunity can be a potential target for the adverse effects of pesticide exposure.

Toxicity of inhaled cadmium chloride: early responses of the antioxidant and surfactant systems in rat lungs.

In order to establish an animal model for assessing early and sensitive biochemical indicators of pulmonary damage, we studied the effects of inhaled CdCl2 (5 mg/m3.h; mass median aerodynamic diameter (MMAD) = 1.4 microns; SDg = 1.8) on the antioxidant defense and pulmonary surfactant systems of rat lungs. Rats were sacrificed 1, 4, 8, and 16 d after inhalation. Pulmonary edema (wet/dry weight) was observed on d 1. The total activities of the enzymes superoxide dismutase (SOD) and glucose-6-phosphate dehydrogenase (G6PD) in the lung homogenates of the treated animals were significantly throughout the 16-d period. Glutathione reductase (GR) was increased on d 4 and after. The general increases of SOD, GR, and the lysosomal enzymes acid phosphatase and beta-N-acetylglucosaminidase could be attributed to changes in the cellularity of the lung tissue. The significant increase in the specific activity of G6PD on d 4 suggested enzyme stimulation. Concurrently, the response of the surfactant system was measured by assaying the alkaline phosphatase (AKP) and the phospholipid content in the homogenates and in the cell-free bronchoalveolar lavage (BAL) fluids. The AKP activity in the homogenates decreased by 30%, while no activity was detected in the BAL on d 1, suggesting an inhibition of AKP by Cd. The secretion of surfactant seemed altered at this early time: phospholipid in the BAL decreased by 44%, although it increased by 61% in the tissue. The high recovery of phospholipid (312%) in the BAL on d 4 and the important changes in the AKP activity in the BAL from d 4 to 16 may reflect alterations in the processing of the surfactant. The effect of Cd on AKP makes this enzyme a potential marker of the metal redistribution in the pulmonary alveolar region, which could be a useful tool in long-term studies.

Immunosuppression in mice after inhalation of cadmium aerosol.

Aerosol cadmium (CdCl2) exposure of female C57Bl/6 mice was performed to assess the in vivo effects of cadmium on the cellular and humoral immune responses of splenic lymphocytes. Primary cellular and humoral responses of lymphocytes were examined at 5-18 days after a single, 60 min exposure to 0.88 mg Cd/m3 (MMAD = 0.7 +/- 0.3 micron, sigma g = 3.43). Significant decrease of in vitro lymphoproliferative response to allogeneic antigens, LPS and PHA antigens, and inhibition of the primary IgM response to sheep erythrocytes were correlated with a marked decrease in spleen cell viability at 5-8 days after aerosol cadmium exposure. This type of cadmium-induced immunosuppression, which correlated with the direct cytotoxicity of effector cells, appeared to be different from the chronic, oral cadmium-induced suppression of the primary IgM response, in which acute cytotoxicity of the spleen cell population was not observed.

Macrophage functional activities versus cellular parameters upon sublethal pesticide exposure in mice.

The toxicity of selected organochlorine, organophosphate, and carbamate pesticides on the functions and cellular parameters of peritoneal macrophages was examined in inbred C57Bl/6 mice. Effects of single, sublethal pesticide exposure on macrophages were determined by analysis of the cell viability, cell adherence capacity, generation of superoxide anion (O2-), antigen processing, phagocytosis of Salmonella typhimurium, and resistance to in vitro virus-induced cytopathic effects (cpe) after infection with mouse hepatitis virus 3 (MHV3). Most of the studies were done for the organochlorine pesticide dieldrin, which inhibited several macrophage functions, such as phagocytosis of S. typhimurium, release of the single processed protein antigen avidin, and resistance to MHV3 virus-induced cpe. The virus-induced cytolysis in macrophage cultures was significantly increased after in vivo exposure to single sublethal doses of other selected pesticides, such as guthion, carbofuran, sevin, and matacil. However, none of the selected pesticides, used in sublethal (0.4 less than or equal to LD50 less than or equal to 0.6) doses appeared to be a factor impairing the O2- -generating system in chemically elicited or immunologically activated peritoneal macrophages. In conclusion, sublethal pesticide exposure can induce a significant impairement of several macrophage functions, such as phagocytosis, antigen processing, and resistance to virus-induced cytolysis. Inhibition of the O2- -generating system by sublethal pesticide exposure, however, can be excluded as a mechanism of potential suppressory action of these pesticides on antiviral and antibacterial host defence systems in which macrophages play a primary role.