Effects of acute stanozolol treatment on puberty in female rats

The effects of anabolic-androgenic steroid (AAS) abuse on the onset of puberty in female adolescents are largely unknown. This study assessed the acute effects of one AAS, stanozolol, on pubertal onset in the female rat. A single injection of stanozolol (5 mg/kg) on Postnatal Day (PN) 21 advanced vaginal opening but did not alter the onset of vaginal estrus. Higher doses of stanozolol treatment (10 and 25 mg/kg) also advanced vaginal opening but had no effect on vaginal estrus. The advancement of vaginal opening by stanozolol (5 mg/kg) was prevented by the concomitant administration of the pure antiestrogen ICI 182,780 (1 mg/kg) on PN20-22. Administration of the androgen receptor antagonist flutamide (10 mg/kg twice daily) on PN20-22 had no effect on the advancement of vaginal opening by stanozolol. Stanozolol treatment also advanced vaginal opening in ovariectomized rats. Perivaginal injections of a low dose of stanozolol (0.05 mg) on PN21 and PN23 also advanced vaginal opening. These results suggest that stanozolol is acting directly at estrogen receptors in the vaginal epithelium to advance vaginal opening and that prepubertal stanozolol treatment does not induce true precocious puberty.     

Enzymes that hydrolyze adenine nucleotides of patients with hypercholesterolemia and inflammatory processes

The activity of NTPDase (EC 3.6.1.5, apyrase, CD39) was verified in platelets from patients with increasing cholesterol levels. A possible association between cholesterol levels and inflammatory markers, such as oxidized low-density lipoprotein, highly sensitive C-reactive protein and oxidized low-density lipoprotein autoantibodies, was also investigated. Lipid peroxidation was estimated by measurement of thiobarbituric acid reactive substances in serum. The following groups were studied: group I, < 150 mg.dL(-1) cholesterol; group II, 151-200 mg.dL(-1) cholesterol; group III, 201-250 mg.dL(-1) cholesterol; and group IV, > 251 mg.dL(-1) cholesterol. The results demonstrated that both ATP hydrolysis and ADP hydrolysis were enhanced as a function of cholesterol level. Low-density lipoprotein levels increased concomitantly with total cholesterol levels. Triglyceride levels were increased in the groups with total cholesterol above 251 mg.dL(-1). Oxidized low-density lipoprotein levels were elevated in groups II, III, and IV. Highly sensitive C-reactive protein was elevated in the group with cholesterol levels higher than 251 mg.dL(-1). Oxidized low-density lipoprotein autoantibodies were elevated in groups III and IV. Thiobarbituric acid reactive substance content was enhanced as a function of cholesterol level. In summary, hypercholesterolemia is associated with enhancement of inflammatory response, oxidative stress, and ATP and ADP hydrolysis. The increased ATP and ADP hydrolysis in group IV was confirmed by an increase in CD39 expression on its surface. The increase in CD39 activity is possibly related to a compensatory response to the inflammatory and pro-oxidative state associated with hypercholesterolemia.     

Enhanced establishment of a virus carrier state in adult CD4+ T-cell-deficient mice.

CD4+ T cells play an important role in regulating the immune response; their contribution to virus clearance is variable. Mice that lack CD4+ T cells (CD4-/- mice) and are therefore unable to produce neutralizing antibodies cleared viscero-lymphotropic lymphocytic choriomeningitis virus (LCMV) strain WE when infected intravenously with a low dose (2 x 10(2) PFU) because of an effective CD8+ cytotoxic T-cell (CTL) response. In contrast, infection with a high dose (2 x 10(6) PFU) of LCMV strain WE led to expansion of antiviral CTL, which disappeared in CD4-/- mice; in contrast, CD4+ T-cell-competent mice developed antiviral memory CTL. This exhaustion of specific CTL caused viral persistence in CD4-/- mice, whereas CD4+ T-cell-competent mice eliminated the virus. After infection of CD4-/- mice with the faster-replicating LCMV strain DOCILE, abrogation of CTL response and establishment of viral persistence developed after infection with a low dose (5 x 10(2) PFU), i.e., an about 100-fold lower dose than in CD(4+)-competent control mice. These results show that absence of T help enhances establishment of an LCMV carrier state in selected situations.     

Loss of CD226 protects apolipoprotein E-deficient mice from diet-induced atherosclerosis

CD226 is a costimulatory molecule that regulates immune cell functions in T cells, natural killer cells, and macrophages. Because macrophage-derived foam cell formation is a crucial factor contributing to the development of atherosclerosis, we aimed to evaluate the potential roles of CD226 in the pathogenesis of atherosclerosis. The effects of CD226 on atherosclerosis were investigated in CD226 and apolipoprotein E double-knockout (CD226^?/? ApoE^?/?) mice fed with a high-cholesterol atherogenic diet. CD226 expression in macrophages was evaluated using flow cytometry. Histopathological analysis was performed to evaluate the atherosclerotic lesions. Inflammatory cell infiltration was detected using immunofluorescence staining. Bone marrow-derived macrophages (BMDMs) and peritoneal macrophages (PEMs) were isolated from the mice and used to explore the mechanism in vitro. The in vivo results indicated that CD226 knockdown protected against atherosclerosis in ApoE^?/? mice, evidenced by reduced plaque accumulation in the brachiocephalic artery, aortic roots, and main aortic tree. CD226 gene-deficient macrophages showed reduced foam cell formation under ox-low density lipoprotein stimulation compared with wild-type (WT) cells. CD226 deficiency also decreased the expression of CD36 and scavenger receptor (SR)-A (responsible for lipoprotein uptake) but increased the expression of ATP-binding cassette transporter A1 and G1 (two transporters for cholesterol efflux). Therefore, loss of CD226 hinders foam cell formation and atherosclerosis progression, suggesting that CD226 is a promising new therapeutic target for atherosclerosis.     

4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T cells in a CD40-dependent manner

4-1BB (CD137) is a member of the TNFR superfamily (TNFRSF9). T cell expression of 4-1BB is restricted to activated cells, and cross-linking has been shown to deliver a costimulatory signal. Here we have shown that treatment of tumor-bearing mice with agonistic 4-1BB-specific Abs can lead to T cell-mediated tumor rejection. In vivo mAb depletion experiments demonstrated that this rejection requires CD8(+) cells but not CD4(+) or NK cells. Both IFN-gamma- and CD40-mediated signals were also required, because no benefit was observed on treatment with 4-1BB mAb in mice in which the genes for these molecules had been knocked out. Interestingly, 4-1BB-mediated stimulation of immune responses in CD40L(-/-) mice is effective (although at a reduced level), and may suggest the existence of an alternative ligand for CD40. Additional experiments in IL-15(-/-) mice indicate that IL-15 is not required for either the generation of the primary tumor-specific immune response or the maintenance of the memory immune response. In contrast, the presence of CD4 cells during the primary immune response appears to play a significant role in the maintenance of effective antitumor memory. Finally, in mice in which the number of dendritic cells had been expanded by Fms-like tyrosine kinase3 ligand treatment, the antitumor effects of 4-1BB ligation were enhanced.     

Dynamic regulation of T cell immunity by CD43

During a viral response, Ag-specific effector T cells show dramatically increased binding by the mAb 1B11 and the lectin peanut agglutinin (PNA). We investigated the contribution of CD43 expression to 1B11 and PNA binding as well as its role in generation and maintenance of a CD8 T cell response. Analysis of CD43(-/-) mice revealed no increased 1B11 binding and reduced PNA binding on virus-specific CD8 T cells from -/- mice compared with +/+ mice. Furthermore, we examined the role of CD43 in the kinetics of an immune response. We show that CD43 expression modestly effects generation of a primary virus-specific CD8 T cell response in vivo but plays a more significant role in trafficking of CD8 T cells to tissues such as the brain. More interestingly, CD43 plays a role in the contraction of the immune response, with CD43(-/-) mice showing increased numbers of Ag-specific CD8 T cells following initial expansion. Following the peak of expansion, Ag-specific CD8 T cells from -/- mice show similar proliferation but demonstrate increased Bcl-2 levels and decreased apoptosis of Ag-specific effector CD8 T cells in vitro. Consistent with a delay in the down-modulation of the immune response, following chronic viral infection CD43(-/-) mice show increased morbidity. These data suggest a dynamic role of CD43 during an immune response: a positive regulatory role in costimulation and trafficking of T cells to the CNS and a negative regulatory role in the down-modulation of an immune response.     

RESPONSIVENESS TO HUMORAL FACTORS OF MOUSE MARROW COLONY FORMING CELLS AFTER TREATMENT WITH CYCLOPHOSPHAMIDE

Humoral factors affecting granulopoiesis have been detected by culturing bone marrow cells in intraperitoneal diffusion chambers. This study investigated the possibility that treatment with drugs alters the ability of cells to respond to these factors. Three days after treatment with 200 mg kg^-1 cyclophosphamide, donor marrow cells were more responsive than normal cells to the factors produced in cyclophosphamide pretreated hosts. The optimum timing of host pretreatment for maximum colony stimulation also differed for cells from cyclophosphamide treated and untreated donors and these effects were found to depend on the dose of drug given to the animals.     

Green tea catechin leads to global improvement among Alzheimer's disease-related phenotypes in NSE/hAPP-C105 Tg mice

Amyloid β (Αβ) has been reported to be responsible for the functional and structural abnormalities of Alzheimer's disease (AD) through the induction of oxidative stress. The aim of this study was to determine whether or not treatment of transgenic (Tg) mice with green tea catechin (GTC), a radical scavenger, improves AD phenotypes. To test this, 7-month-old Tg mice were treated with a low (1 mg) or high (10 mg) dose of GTC for 6 months. Surprisingly, GTC-treated Tg mice exhibited significant decreases in behavioral impairment, Aβ-42 production, APP-C99/89 expression, γ-secretase component and Wnt protein levels, γ-secretase activity and MAPK activation. In contrast, the levels of APP-C83 protein and enzyme activities (α-secretase, neprilysin and Pin1) were elevated in the GTC-treated groups. Moreover, GTC-treated groups showed lower levels of total cholesterol and low-density lipoprotein cholesterol, whereas the level of high-density lipoprotein cholesterol increased. These results provide the first experimental evidence that GTC improves AD phenotypes, thereby suggesting that GTC can be used in the prevention of AD or treatment of AD patients.     

Deleterious effects of potassium bromate administration on renal and hepatic tissues of Swiss mice

Potassium bromate (KBrO₃) is widely used as a food additive and is a major water disinfection by-product. The present study reports the side effects of KBrO₃ administration in Swiss mice. Animals were randomly divided into three groups: control, low dose KBrO₃ (100 mg/kg/day) and high dose KBrO₃ (200 mg/kg/day) groups. Administration of KBrO₃ led to decreased white blood corpuscles (WBCs), red blood corpuscles (RBCs) and platelets count in the animals of both the high and the low dose groups. Altered lipid profile represented as low density lipoprotein (LDL), high density lipoprotein (HDL) and cholesterol levels were observed in plasma samples of both KBrO₃ treated groups of mice. Also, an increased plasma level of LDH was detected in both KBrO₃ treated groups. Histological investigations showed impaired renal and hepatic histology that was concomitant with increased plasma Creatinine level in both of KBrO₃-treated groups. Nevertheless, decreased glutathione (GSH) level in both renal and hepatic tissue of mice after KBrO₃ intake was detected. These results show that KBrO₃ has serious damaging effects and therefore, its use should be avoided.     

Diminished primary and secondary influenza virus-specific CD8(+) T-cell responses in CD4-depleted Ig(-/-) mice

Optimal expansion of influenza virus nucleoprotein (D(b)NP(366))-specific CD8(+) T cells following respiratory challenge of naive Ig(-/-) microMT mice was found to require CD4(+) T-cell help, and this effect was also observed in primed animals. Absence of the CD4(+) population was consistently correlated with diminished recruitment of virus-specific CD8(+) T cells to the infected lung, delayed virus clearance, and increased morbidity. The splenic CD8(+) set generated during the recall response in Ig(-/-) mice primed at least 6 months previously showed a normal profile of gamma interferon production subsequent to short-term, in vitro stimulation with viral peptide, irrespective of a concurrent CD4(+) T-cell response. Both the magnitude and the localization profiles of virus-specific CD8(+) T cells, though perhaps not their functional characteristics, are thus modified in mice lacking CD4(+) T cells.     

Effects of chronic anabolic steroid treatment on tonic and reflex cardiovascular control in male rats

The aim of this study was to analyze the cardiovascular effects of chronic stanozolol administration in male rats. The rats were randomly assigned to one of three groups: (1) control (n=12), (2) chronic treatment with low dose of stanozolol (LD, n=18, 5 mg/kgweek) and; (3) treatment with high dose of stanozolol (HD, n=28, 20 mg/kgweek). Mean arterial pressure (MAP) was higher in both HD (128+/-2.2 mmHg) and LD (126+/-2.5 mmHg) than control (116+/-2 mmHg). The LD group showed an increase in cardiac output (control 121+/-2.5, LD 154+/-5.9 ml/min), whereas in the HD group total peripheral resistance increased (control 1.03+/-0.07, HD 1.26+/-0.07 mmHg/ml/min). Acute sympathetic blockade caused a similar decrease in MAP in all groups. In conscious rats, the baroreflex index for bradycardia (control -3.7+/-0.4, LD -2.0+/-0.1 beat/mmHg) and tachycardia (control -3.6+/-0.3, LD -4.7+/-0.2 beat/mmHg) responses changed only in the LD group. Cardiac hypertrophy was observed in both treated groups (P<0.05). In conclusion, hypertension with differential hemodynamic changes and alterations in the reflex control in heart rate is seen at different stanozolol doses, which may be important variables in the cardiovascular effects of anabolic steroids.     

CD28/B7 regulation of anti-CD3-mediated immunosuppression in vivo

FcR-binding "classical" anti-CD3 mAb is a potent immunosuppressive drug that alters CD4(+) and CD8(+) T cell function in vivo via anergy induction and programmed cell death (PCD). Anti-CD3-mediated PCD was Fas independent but was mediated by the mitochondria-initiated apoptosis that was abrogated in Bcl-x(L)-transgenic T cells. The PCD was more pronounced in CD28-deficient mice consistent with defective Bcl-x(L) up-regulation. Residual T cells isolated from anti-CD3-treated wild-type, CD28(-/-), and Bcl-x(L)-transgenic mice were hyporesponsive. The hyporesponsiveness was more pronounced in CD28(-/-) and wild-type mice treated with anti-B7-2, suggesting that CD28 interaction with B7-2 regulates T cell responsiveness in anti-CD3-treated animals. Finally, anti-CD3 treatment led to indefinite cardiac allograft survival in wild-type but not Bcl-x(L) animals. Together these results implicate CD28/B7 signaling in the regulation of both anti-CD3-induced T cell depletion and hyporesponsiveness in vivo, but T cell depletion, not hyporesponsiveness, appears to be critical for anti-CD3 mAb-mediated long-term immune regulation.     

Macrophage PLTP is atheroprotective in LDLr-deficient mice with systemic PLTP deficiency

Systemic phospholipid transfer protein (PLTP) is a recognized risk factor for coronary heart disease. In apolipoprotein E-deficient mice, systemic PLTP deficiency is atheroprotective, whereas PLTP overexpression is proatherogenic. As expected, we also observed significantly smaller lesions (P < 0.0001) in hypercholesterolemic double mutant low density lipoprotein receptor-deficient (LDLr(-/-)) PLTP-deficient (PLTP(-/-)) mice compared with LDLr(-/-) mice expressing systemic PLTP. To assess the specific contribution of only macrophage-derived PLTP to atherosclerosis progression, bone marrow transplantation was performed in LDLr(-/-) mice that also lacked systemic PLTP. Groups of double mutant PLTP(-/-)LDLr(-/-) mice were irradiated with 1,000 rad and injected with bone marrow (BM) cells collected from either PLTP(-/-) or wild-type mice. When fed a high-fat diet, BM cell expression of PLTP decreased plasma cholesterol of PLTP(-/-)LDLr(-/-) mice from 878 +/- 220 to 617 +/- 183 mg/dl and increased HDL cholesterol levels from 54 +/- 11 to 117 +/- 19 mg/dl. This decreased total plasma cholesterol and increased HDL cholesterol contributed to the significantly smaller atherosclerotic lesions in both aortas and heart sinus valves observed in these mice. Thus, unlike total systemic PLTP, locally produced macrophage-derived PLTP beneficially alters lipoprotein metabolism and reduces lesion progression in hyperlipidemic mice.     

A switch in costimulation from CD28 to 4-1BB during primary versus secondary CD8 T cell response to influenza in vivo

4-1BBL(-/-) mice exhibit normal primary CD8 T cell responses to influenza virus, but show decreased CD8 T cell numbers late in the primary response as well as decreased secondary responses. In contrast, CD28(-/-) mice are defective in initial CD8 T cell expansion. Using agonistic anti-4-1BB Ab to replace the CD28 or 4-1BB signal, we examined the timing of the required signals for CD28 vs 4-1BB costimulation. A single dose of agonistic anti-4-1BB Ab added only during priming restores the secondary CD8 T cell response in CD28(-/-) mice. Once the T cell numbers in the primary response reach a minimum threshold, a full secondary response is achieved even in the absence of CD28. In contrast, anti-4-1BB added during priming fails to correct the defective secondary response in 4-1BBL(-/-) mice, whereas addition of anti-4-1BB during challenge fully restores this response. Thus, there is a switch in costimulatory requirement from CD28 to 4-1BB during primary vs recall responses. Adoptive transfer studies show that T cells primed in 4-1BBL(-/-) or wild-type mice are equally capable of re-expansion when rechallenged in wild-type mice. These studies rule out a model in which signals delivered through 4-1BB during priming program the T cells to give a full recall response and suggest that 4-1BB-4-1BBL interactions take place at later stages in the immune response. The results indicate that anti-4-1BB or 4-1BBL therapy will be most effective during the boost phase of a prime-boost vaccination strategy.     

Th1-Biased Immunomodulation and Therapeutic Potential of Artemisia annua in Murine Visceral Leishmaniasis

Background

In the absence of vaccines and limitations of currently available chemotherapy, development of safe and efficacious drugs is urgently needed for visceral leishmaniasis (VL) that is fatal, if left untreated. Earlier we reported in vitro apoptotic antileishmanial activity of n-hexane fractions of Artemisia annua leaves (AAL) and seeds (AAS) against Leishmania donovani. In the present study, we investigated the immunostimulatory and therapeutic efficacy of AAL and AAS.

Methodology/Principal Findings

Ten-weeks post infection, BALB/c mice were orally administered AAL and AAS for ten consecutive days. Significant reduction in hepatic (86.67% and 89.12%) and splenic (95.45% and 95.84%) parasite burden with decrease in spleen weight was observed. AAL and AAS treated mice induced the strongest DTH response, as well as three-fold decrease in IgG1 and two-fold increase in IgG2a levels, as compared to infected controls. Cytometric bead array further affirmed the elicitation of Th1 immune response as indicated by increased levels of IFN-γ, and low levels of Th2 cytokines (IL-4 and IL-10) in serum as well as in culture supernatant of lymphocytes from treated mice. Lymphoproliferative response, IFN-γ producing CD4⁺ and CD8⁺ T lymphocytes and nitrite levels were significantly enhanced upon antigen recall in vitro. The co-expression of CD80 and CD86 on macrophages was significantly augmented. CD8⁺ T cells exhibited CD62L^low and CD44^hi phenotype, signifying induction of immunological memory in AAL and AAS treated groups. Serum enzyme markers were in the normal range indicating inertness against nephro- and hepato-toxicity.

Conclusions/Significance

Our results establish the two-prong antileishmanial efficacy of AAL and AAS for cure against L. donovani that is dependent on both the direct leishmanicidal action as well as switching-on of Th1-biased protective cell-mediated immunity with generation of memory. AAL and AAS could represent adjunct therapies for the treatment of leishmaniasis, either alone or in combination with other antileishmanial agents.     

Upregulation of ICOS on CD43+ CD4+ murine small intestinal intraepithelial lymphocytes during acute reovirus infection

Murine intestinal intraepithelial lymphocytes (IELs) can be classified according to expression of a CD43 glycoform recognized by the S7 monoclonal antibody. In this study, we examined the response of S7+ and S7- IELs in mice during acute reovirus serotype 3 (Dearing strain) infection, which was confirmed by virus-specific real-time PCR. In vivo proliferation increased significantly for both S7- and S7+ IELs on day 4 post-infection as determined by BrdU incorporation; however, expression of the inducible costimulatory (ICOS) molecule, which peaked on day 7 post-infection, was upregulated on S7+ CD4+ T cells, most of which were CD4+8- IELs. In vitro ICOS stimulation by syngeneic peritoneal macrophages induced IFN-gamma secretion from IELs from day 7 infected mice, and was suppressed by treatment with anti-ICOS mAb. Additionally, IFN-gamma mRNA increased in CD4+ IELs on day 6 post-infection. These findings indicate that S7- and S7+ IELs are differentially mobilized during the immune response to reovirus infection; that the regulated expression of ICOS is associated with S7+ IELs; and that stimulation of IELs through ICOS enhances IFN-gamma synthesis during infection.     

Responsiveness to humoral factors of mouse marrow colony forming cells after treatment with cyclophosphamide.

Humoral factors affecting granulopoiesis have been detected by culturing bone marrow cells in intraperitoneal diffusion chambers. This study investigated the possibility that treatment with drugs alters the ability of cells to respond to these factors. Three days after treatment with 200 mg kg-1 cyclophosphamide, donor marrow cells were more responsive than normal cells to the factors produced in cyclophosphamide pretreated hosts. The optimum timing of host pretreatment for maximum colony stimulation also differed for cells from cyclophosphamide treated and untreated donors and these effects were found to depend on the dose of drug given to the animals.     

Role of CD40 ligand and CD28 in induction and maintenance of antiviral CD8+ effector T cell responses

The primary aim of this report was to evaluate the immune responses of CD40 ligand-deficient (CD40L-/-) mice infected with two viruses known to differ markedly in their capacity to replicate in the host. Lymphocytic choriomeningitis virus (LCMV) is a natural mouse pathogen that replicates widely and extensively, whereas vesicular stomatitis virus (VSV) spreads poorly. We found that the primary response of CD40L-/- mice toward VSV is significantly impaired; proliferation of both CD4+ and CD8+ cells is reduced 2- to 3-fold, few CD8+ cells acquire an activated phenotype, and little functional activity is induced. Very similar results were obtained in VSV-infected, CD28-deficient mice. In contrast, neither CD40L nor CD28 was required for induction of a primary CD8+ response toward LCMV. Surprisingly, lack of CD4+ T cells had no impact on the primary immune response toward any of the viruses, even though the CD40 ligand dependence demonstrated for VSV would be expected to be associated with CD4 dependence. Upon coinfection of VSV-infected mice with LCMV, the requirement for CD40 ligand (but not CD28) could be partially bypassed, as evidenced by a 3-fold increase in the frequency of VSV-specific CD8+ T cells on day 6 postinfection. Finally, despite the fact that the primary LCMV-specific CD8+ response is virtually unimpaired in CD40L-/- mice, their capacity to maintain CD8+ effector activity and to permanently control the infection is significantly reduced. Thus, our results demonstrate that the importance of CD40/CD40L interaction for activation of CD8+ T cells varies between viruses and over time.     

Effect of millimeter waves on cyclophosphamide induced suppression of T cell functions

The effects of low power electromagnetic millimeter waves (MWs) on T cell activation, proliferation, and effector functions were studied in BALB/c mice. These functions are important in T-lymphocyte mediated immune responses. The MW exposure characteristics were: frequency = 42.2 GHz; peak incident power density = 31 +/- 5 mW/cm(2), peak specific absorption rate (SAR) at the skin surface = 622 +/- 100 W/kg; duration 30 min daily for 3 days. MW treatment was applied to the nasal area. The mice were additionally treated with cyclophosphamide (CPA), 100 mg/kg, a commonly used immunosuppressant and anticancer drug. Four groups of animals were used in each experiment: naive control (Naive), CPA treated (CPA), CPA treated and sham exposed (CPA + Sham), and CPA treated and MW exposed (CPA + MW). MW irradiation of CPA treated mice significantly augmented the proliferation recovery process of T cells (splenocytes). A statistically significant difference (P <.05) between CPA and CPA + MW groups was observed when cells were stimulated with an antigen. On the other hand, no statistically significant difference between CPA and CPA-Sham groups was observed. Based on flow cytometry of CD4(+) and CD8(+) T cells, two major classes of T cells, we show that CD4(+) T cells play an important role in the proliferation recovery process. MW exposure restored the CD25 surface activation marker expression in CD4(+) T cells. We next examined the effector function of purified CD4(+) T cells by measuring their cytokine profile. No changes were observed after MW irradiation in interleukin-10 (IL-10) level, a Th2 type cytokine, while the level of interferon-gamma (IFN-gamma), a Th1 type cytokine was increased twofold. Our results indicate that MWs enhance the effector function of CD4(+) T cells preferentially, through initiating a Th1 type of immune response. This was further supported by our observation of a significant enhancement of tumor necrosis factor-alpha (TNF-alpha) production by peritoneal macrophage's in CPA treated mice. The present study shows MWs ameliorate the immunosuppressive effects of CPA by augmenting the proliferation of splenocytes, and altering the activation and effector functions of CD4(+) T cells.     

Leukocyte CD11b expression is not essential for the development of atherosclerosis in mice

CD11b is an alpha chain of the leukocyte beta(2)-integrin, Mac-1, which mediates binding and extravasation of leukocytes. Because this event is critical in atherosclerosis, we examined the role of CD11b in lesion formation. Atherosclerosis-susceptible, low density lipoprotein receptor-deficient (LDL-R(-/)-) mice were irradiated and repopulated with bone marrow cells from CD11b-deficient (CD11b(-/)-) mice. After 4 weeks, <2% of the peripheral blood leukocytes of the CD11b(-/)- bone marrow-transplanted LDL-R(-/)- mice expressed CD11b, whereas approximately 25% of the CD11b(+/)+ bone marrow-transplanted LDL-R(-/)- mice expressed CD11b. After consuming a high-fat diet for 16 weeks the mean lesion aortic valve area, cholesterol accumulation in the aorta, and the degree of intimal macrophage infiltration were similar in mice reconstituted with either CD11b(+)(/+) or CD11b(-/)- bone marrow cells.The studies confirm that CD11b expression of bone marrow-derived cells does not influence the development of atherosclerosis in hypercholesterolemic LDL-R(-/)- mice.