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PubMedDate not supplied

Practical aspects of including functional endpoints in developmental toxicity studies. Case study: immune function in HuCD4 transgenic mice exposed to anti-CD4 MAb in utero.

Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. As the preclinical safety assessment of biopharmaceuticals requires evaluation in pharmacologically responsive species, comprehensive toxicology studies, including reproductive toxicity, of this antibody were conducted in a human CD4 transgenic mouse model. The reproductive toxicology studies included a pre- and postnatal development study that incorporated immunotoxicological evaluation of offspring (F1) mice. The potential effects of exposure to treating maternal mice (F0) with keliximab during pregnancy and lactation on offspring viability, physical growth, neurobehavioral development, reproductive function, lymphoid tissue morphological structure, lymphocyte subsets and host resistance to Candida albicans infection were assessed. The results showed no impairment of these functions. The use of F1 transgenic mice in study with keliximab provides an example of a novel practical approach to assess developmental immunotoxicity within a study of pre- and postnatal development designed in accordance with ICH Guidelines.

Age Factors↗
PubMed1993

Immune function in offspring of nonhuman primates (Macaca nemestrina) exposed weekly to 1.8 g/kg ethanol during pregnancy: preliminary observations.

A preliminary investigation of immune host response was conducted in a group of fetal alcohol-exposed nonhuman primates (Macaca nemestrina) who were part of a broader ongoing study of ethanol teratogenicity. The mothers of the offspring received weekly oral doses of ethanol (1.8 g/kg) for the first 3 or 6 or the entire 24 weeks of gestation. A control group received sucrose solution weekly throughout pregnancy. Four of the 18 ethanol-exposed animals (22%) died or were euthanized after infectious disease or failure to thrive during the first year of life; none of the seven control animals died. This imbalance in survival prompted the present review of immune function in the remaining offspring. Parameters assessed included: (1) white blood cell count (WBC), (2) peripheral blood leucocyte subsets (CD4+, CD8+, CD20+, and CD11c+), (3) T-cell proliferation after activation with phytohemagglutinin (PHA), staphylococcus enterotoxin B (SEB), and tetanus toxoid (TT), (4) phagocytic activity of monocytes, and (5) serum immunoglobulin levels and serum antibody titers after TT vaccination. Mean T-cell proliferation to TT was significantly decreased (p = 0.01) in all ethanol-exposed animals relative to controls, with near-significant decreases (p = 0.06) in response to SEB in the ethanol-exposed animals. Lymphocyte proliferation in response to PHA was not altered. Ethanol-exposed animals had significantly lower TT titers than controls after initial vaccination and booster. WBC, leukocyte subsets, serum immunoglobulins, and monocyte phagocytic activity were not significantly different from control values. These preliminary observations suggest that T-cell proliferation and antigen-specific memory responses may be altered in offspring exposed to weekly doses of ethanol in utero and warrant further evaluation for confirmation.

Animals↗
PubMed1991

[Effect of kang shuai shen fang on immune functions of 60Co gamma-ray irradiated mice].

In this paper we reported that kang shuai shen fang (KSSF) could recover the immune functions of irradiated mice. The results indicated that KSSF is able to enhance the proliferation response of spleen cells of irradiated mice to Con A and LPS. At the dosage of 400 mg/kg.d, KSSF can stimulate the production of plaque forming cells, the DTH response induced by allogeneic splenocytes. The mixed lymphocyte reaction was much stronger in the drug-receiving irradiated group than that in the control group. Further study indicated that KSSF is able to enhance the production of interleukin 2 in irradiated mice.

Animals↗
PubMed1995

Immune functions of spleen lymphocytes of rats subjected to chronic irradiation and antioxidant (ubiquinone Q-9) diet.

The dynamics of T and B cell immunity in spleens from rat exposed to whole-body chronic irradiation with dose rates of 12.9 cGy/day (range 1-10 Gy) and 3.0 cGy/day (range 0.57-2.04 Gy) were investigated. gamma-irradiation with a dose-rate of 12.9 cGy/day was shown to produce a wave-like suppression of the T lymphocyte mitogenic response. Irradiation with a dose-rate of 3.0 cGy/day caused a decrease in immune response of T lymphocytes 48 days after onset of exposure (total dose 1.4 Gy). It was also shown that chronic irradiation with a dose-rate of 3.0 cGy/day produced significant changes in the DNA of T lymphocytes. Our results show that the radiation-induced suppression of immune functions and damage to DNA structure were partially eliminated when animals were fed a daily diet supplemented with a natural antioxidant, ubiquinone Q-9. The inhibiting effect of chronic irradiation was more pronounced in B lymphocytes because of their higher radiosensitivity.

Animals↗
PubMed2002

Endomorphins 1 and 2 inhibit IL-10 and IL-12 production and innate immune functions, and potentiate NF-kappaB DNA binding in THP-1 differentiated to macrophage-like cells.

We evaluated immunological effects of opioid peptides endomorphins 1 and 2 on the production of interleukin-10 (IL-10) and IL-12 cytokines, functions related to innate immunity and NF-kappaB DNA binding in human cell line THP-1. Endomorphins 1 and 2 inhibited lipopolysaccharide (LPS)-stimulated IL-10 and IL-12 production in THP-1 differentiated to macrophage-like cells by phorbol 12-myristate 13-acetate (PMA). Similarly, they suppressed LPS-stimulated IL-10 and IL-12 production in THP-1 matured to monocytes by 1alpha,25-dihydroxyvitamin D3. In addition, endomorphins 1 and 2 led to marked potentiation of NF-kappaB binding in THP-1 differentiated to macrophage-like cells. Furthermore, these endomorphins further potentiated LPS-induced NF-kappaB binding. Moreover, they inhibited chemotaxis, phagocytosis of Escherichia coli and PMA-stimulated production of hydrogen peroxide in THP-1 differentiated to macrophage-like cells. These results suggest that endomorphins 1 and 2 may inhibit THP-1 functions, such as cytokine production and functions related to innate immune, and potentiate NF-kappaB DNA binding in THP-1.

Cell Differentiation↗
PubMed2006

[Effects of injection of Huangqi injectio into Zusanli (ST 36) on immune function in the patient of schizophrenia].

OBJECTIVE: To study on effects of injection of Huangqi Injectio into Zusanli (ST 36) on the hospital infection and immune function in the patient of schizophrenia. METHODS: Thirty inpatients of chronic schizophrenia were treated with injection of Huangqi Injectio into bilateral Zusanli (ST 36), 2 mL each point, thrice each week, for 8 weeks. Relative immune indexes and the hospital infection were investigated. RESULTS: The hospital infection and the sub-infection were 4 cases (13.3%), 7 cases-times (23.3%) in the injection group; and 9 cases (15.0%), 19 cases-times (31.7%) in the control group, respectively, with no significant difference between the two groups (P>0.05). The drug-administration duration was 7.77 days/case and 11.87 days/case in the two groups, respectively (P<0.01). In the injection group, as compared with that of last 3 years the duration was 7.77 days/case and 14.08 days/case (P<0.01). IgG, IgA, IgM and T-cell subgroups did not have significant changes, but there was the most different value before and after injection in SIL-2R of the no-infection group, and the longer the drug administration duration, the smaller the different values. CONCLUSION: Injection of Huangqi Injectio into Zusanli (ST 36) has definite effect for prevention of the hospital infection in inpatients of chronic schizophrenia, and SIL-2R is a valuable index for investigation of the hospital of infection.

Acupuncture Points↗
PubMed2001

Effect of dietary cabbage fermentation extract and young barley leaf powder on immune function of Sprague-Dawley rats.

We investigated dietary effects of cabbage fermentation extract (CFE) and young barley leaf powder (YBLP) on rat immune functions. Male Sprague-Dawley rats of 4 wk age were fed for 3 wk diets containing these samples at 0.1 or 1% level. After the feeding period, serum IgG level was significantly higher in the rats fed 1% CFE. IgG productivity of spleen lymphocytes was enhanced dose-dependently in both groups of CFE and YBLP. Furthermore, IgG productivity of mesenteric lymph node (MLN) lymphocytes was approximately 2 times higher in the rats fed 1% CFE diet than in the control ones. IgA productivity of MLN lymphocytes tended to increase in both of CFE and YBLP groups. From these results, it was suggested that dietary CFE and YBLP reinforced Ig productivity in both systemic and intestinal immune systems. Moreover, CFE feeding tended to enhance the production of TNF-alpha by spleen lymphocytes. In spleen phospholipids, the level of arachidonic acid, a substrate for inflammatory lipid mediators, was not affected by CFE or YBLP feeding.

Animals↗
PubMed2001

Nutrient partitioning between reproductive and immune functions in animals.

The physiological processes that underlie the reproductive cycle impose considerable metabolisable protein (MP) demands on a female, especially during the periparturient period. When MP supply falls short of MP demand (i.e. MP becomes scarce), certain, if not all, bodily functions are expected to be penalised. It has been proposed that partitioning of scarce MP is prioritised to reproductive rather than to immune functions. In other words, at times of MP scarcity, the penalty on expression of immunity would be expected to be greater than that on reproduction. This hypothesis forms a nutritional basis for the occurrence of periparturient breakdown of immunity to parasites (BIP), which can be observed in many host-parasite systems. In the present review we explore this nutritional basis, using periparturient sheep infected with the abomasal nematode Teladorsagia circumcincta as an example, and attempt to quantify its occurrence. Evidence supporting the nutritional basis of periparturient BIP is reviewed, covering experiments in which nutrient supply (from both exogenous and endogenous sources) and/or nutrient demand were manipulated. Quantitatively, MP requirements for expression of immunity to T. circumcincta were estimated to be about 1 g/kg metabolic body weight (body weight 0.75) per d, approximately 5% of the maximum MP requirements of periparturient sheep. The major component of this requirement was assumed to be for replenishing irreversible plasma protein losses into the gastrointestinal tract. Although confirmation of this estimate is required, such estimates may be used to improve the known MP requirements of periparturient animals, enabling the extent and the consequences of periparturient BIP to be minimised.

Animal Nutritional Physiological Phenomena↗
PubMed1989

Combined grafting of bone marrow and thymus, and sequential multiple thymus graftings in various strains of mice. The effect on immune functions and life span.

The combined grafting of young bone marrow and newborn thymus performed in old mice was effective in restoring the impaired immune functions, but the same treatment performed in middle-aged adult mice had no effect on the life span of C3H/MTV female mice. Sequential multiple newborn thymus graftings starting at young adult age were effective in enhancing immunological functions, delaying the onset of tumor and extending the survival rate to certain degree in the first half of the experimental course in both C3H/MTV as well as C57BL/6 mice, but these effects were not observed in the latter half of the experimental course. It was suggested that multiple newborn thymuses sequentially implanted into the peritoneal cavity underwent atrophy and these atrophic thymuses had a suppressive effect on the host immune system. In autoimmune prone B/WF1 mice, however, the combined grafting of young bone marrow and newborn thymus resulted in suppression of antibody formation to SRBC, and single grafting of either young bone marrow or newborn thymus resulted in a trend of increase in the antibody formation to SRBC. The sequential multiple newborn thymus graftings in B/WF1 mice brought about aggravation of kidney diseases and shortening of the mean life span. On the contrary, administration of thymosin in B/WF1 mice resulted in amelioration of kidney disease and elongation of the mean life span.

Animals↗
PubMedDate not supplied

Proliferative and cytotoxic immune functions in aging mice. III. Exogenous interleukin-2 rich supernatant only partially restores alloreactivity in vitro.

The ability of exogenous interleukin-2 (IL-2) rich supernatant to restore the defective T cell mediated immune functions of spleen cells from aged C57BL/6 mice was analyzed. Addition of IL-2 rich supernatant to allogeneic mixed lymphocyte cultures (MLC) resulted in an increase in the proliferative response of spleen cells from both young and old mice. The MLC response of cells from old mice was, however, not restored to the level of proliferation seen with splenocytes from young animals. In studying the generation of specific T cell suppressor function, it was found that IL-2 rich supernatant enhanced this function only for spleen cells from those aged animals which demonstrated a defective response in its absence. The response of these mice was thereby restored to the normal level. The response of cells from young control animals and aged mice with normal suppressor activity was not affected by the addition of IL-2 rich supernatant. We conclude that decreased IL-2 production constitutes a functionally important aspect, but is by no means the only defect in the immune response of aged mice. The results also suggest that responsiveness to IL-2 is less affected by age than lymphokine production.

Aging↗
PubMed2004

Sustained suppression of peripheral blood immune functions by treatment with mycophenolate mofetil correlates with reduced severity of cardiac allograft rejection.

BACKGROUND: We tested the hypothesis that sustained suppression of immune functions by mycophenolate mofetil (MMF) throughout the dosing interval reduces the severity of rejection. METHODS: Four groups of rat heart allograft recipients were treated orally daily through Day 5 with either: "low-dose" MMF, 10 mg/kg once daily (QD) or 5 mg/kg twice daily (BID); or "high-dose" MMF, 20 mg/kg QD or 10 mg/kg BID. The following were determined for all animals on Day 6: pharmacokinetics (PK, using high-performance liquid chromatography) of mycophenolic acid (MPA); pharmacodynamics (PD, by flow cytometry quantitation of whole blood mitogen-stimulated lymphocyte proliferation and expression of diverse T-cell surface activation molecules); and histologic graft rejection scores (RS). RESULTS: RS correlated with PD for suppression of both lymphocyte proliferation and transferrin receptor expression (r2 = 0.85 and 0.81, respectively) more highly than with MPA plasma levels (r2 = 0.45), which shows the validity of PD as surrogate markers of MMF efficacy. MMF 5 mg/kg BID produced greater (p < 0.001) suppression of lymphocyte proliferation (area under the PD effect-time curve, AUE = 2,010% inhibition. hour) and sustained trough (E0) PD effect (86% suppression) than MMF 10 mg/kg QD (AUE = 1,436% inhibition. hour, E0 = 55%). RS did not differ between the 20 mg/kg QD and 10 mg/kg BID "high-dose" groups, because PD was maximally suppressed. CONCLUSIONS: PD were surrogate markers for MMF immunosuppressive efficacy. MMF 5 mg/kg BID produced more sustained suppression of both PD and rejection than MMF 10 mg/kg QD.

Animals↗
PubMed1998

Metoclopramide: a novel and safe immunomodulating agent for restoring the depressed macrophage immune function after hemorrhage.

BACKGROUND AND OBJECTIVE: Recent studies have shown that administration of the anterior pituitary hormone, prolactin, after hemorrhage restored the depressed immune responses that are observed under those conditions. Because metoclopramide (MCP) is known to increase prolactin secretion and ultimately plasma prolactin levels, we attempted to determine whether administration of metoclopramide after hemorrhage produces any beneficial effects on the depressed splenocyte and peritoneal macrophage immune function after severe hemorrhage. DESIGN, MATERIALS AND METHODS: Mice were bled to and maintained at a mean arterial pressure of 35 mm Hg for 60 minutes, then adequately resuscitated and segregated into two groups. One group received saline vehicle; animals in the other group were treated with metoclopramide (100 microg/100 g body weight, subcutaneously) before resuscitation. Two hours after saline or MCP injection, the animals were killed and macrophage as well as splenocyte cultures established. Plasma corticosterone levels were also measured. RESULTS: The proliferative capacity of the splenocytes as well as their ability to release interleukin (IL)-2 and IL-3 in response to mitogen was markedly improved in animals that had hemorrhaged and that were treated with MCP compared with saline-injected mice. Moreover, the depressed splenic and peritoneal macrophage IL-1 and IL-6 release after hemorrhage was restored with MCP treatment. Furthermore, treatment with MCP prevented the increase in blood corticosterone levels seen after severe hemorrhage. CONCLUSION: These results support the concept that the immunosuppression after hemorrhage may be mediated by hormones from the hypothalamic-pituitary-adrenal axis. Furthermore, MCP may be a useful adjuvant in the treatment of the trauma-hemorrhagic shock-induced immunosuppression.

Animals↗
PubMed1998

[Significance and correlation of T lymphocyte subgroup, erythrocyte immune function and argyrophilic protein in nucleolar organizer regions in tuberculosis patients].

OBJECTIVE: To study the significance and relationship of T lymphocyte subgroups, erythrocyte immune functions and argyrophilic protein in nucleolar organizer regions (AgNORs) in tuberculosis patients. METHOD: CD3+, CD4+, CD3+/CD4+ were determined using alkaline phosphatase-antialkaline phosphatase (APAAP) method, E-C3bRR and E-ICR were assayed by observing receptor rate. Granules area of AgNORs (GA) and nuclear area (NA) were studied by image analysis system. RESULT: CD3+, CD4+, CD4+/CD8+, E-C3bRR, GA/NA in tuberculosis patients were significantly lower than those in the healthy group (P < 0.001). However, the values of E-ICR, CD8+ were significantly higher than those of control group (P < 0.001). CONCLUSION: The results of T lymphocyte subgroup, erythrocyte functions and AgNORs are in accord, and might be usefull in assessing diagnosis and prognosis of tuberculosis.

Adult↗
PubMed2002

Effect of blood transfusion during radiotherapy on the immune function of patients with cancer of the uterine cervix: role of interleukin-10.

PURPOSE: To analyze prospectively the effects of blood transfusion administered during radiotherapy (RT) on the immune function of patients with locally advanced cervical cancer. METHODS AND MATERIALS: In a total of 15 patients, 7 transfused and 8 untransfused, lymphocyte populations, including CD3+, CD4+, and CD8+ T-cell subsets, B cells (CD19+), and natural killer (NK) cells (CD56+, CD16+, CD3-) were studied before (i.e., time 0), during (i.e., times 1 and 2), and after (i.e., time 3) therapy. Expression of the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells, the intracellular levels of perforin in CD8+ and CD56+ cells, and interferon (IFN)-gamma, interleukin (IL)-2, and IL-4 in CD4+ and CD8+ T cells were also measured. NK cell cytotoxicity against the NK-sensitive target K-562 cells and CD8+ T-cell-directed cytotoxicity against OKT3 hybridoma cells were also assessed. Finally, the plasma levels of the immunoregulatory cytokine IL-10 were analyzed by enzyme-linked immunosorbent assay. RESULTS: The mean absolute number of all lymphocyte subsets compared with pretreatment levels decreased significantly during RT of both transfused and untransfused patients (p >0.001), with no detectable differences between the two groups in terms of total lymphocytes or relative numbers of CD3+ and CD4+ T cells, CD56+ NK cells, or CD19+ B cells. In contrast, concomitant with an inversion of the CD4/CD8 ratio, a significant increase in the number of CD8+ T cells at time 2 and CD3+ T cells, CD8+ T cells, and NK cells at time 3 was found in the transfused patients compared with the untransfused group. The percentages of CD25+/CD3+ T cells and HLA-DR+/CD3+ T cells increased during RT of the untransfused patients, but CD3+ T cells showed decreased CD25 expression and increased HLA-DR expression in the transfused group. An increase of CD8+ IFN-gamma+ T cells with a concomitant decrease in CD8+ IL-2+ T cells was found in the transfused vs. untransfused group, and no differences were noted in the percentage of CD4+ IFN-gamma+ T cells and CD4+ IL-2+ T cells. The proportion of perforin-positive CD8+ and CD56+ cells was higher in the transfused group than in the untransfused group. However, CD56+ cells and CD8+ T cells from the transfused patients showed markedly diminished cytotoxic function. Finally, IL-10 was detected only in the plasma of the transfused patients. CONCLUSION: Blood transfusion during primary RT for cervical cancer profoundly alters the magnitude and characteristics of radiation-induced immunosuppression. Elevated serum IL-10 in transfused patients may play a role in the disregulation of lymphocyte function, in particular, the depression of NK- and T-cell cytotoxicity. Investigation of alternatives to blood transfusion during RT that do not diminish host immunity is warranted.

Adult↗
PubMed2006

[Induction of glutathione and activation of immune functions by low-dose, whole-body irradiation with gamma-rays].

We first examined the relation between the induction of glutathione and immune functions in mice after low-dose gamma-ray irradiation. Thereafter, inhibition of tumor growth by radiation was confirmed in Ehrlich solid tumor (EST)-bearing mice. The total glutathione level of the splenocytes transiently increased soon after irradiation and reached a maximum at around 4 h postirradiation. Thereafter, the level reverted to the 0 h value by 24 h postirradiation. A significantly high splenocyte proliferative response was also recognized 4 h postirradiation. Natural killer (NK) activity was also increased significantly in a similar manner. The time at which the response reached the maximum coincided well with that of maximum total glutathione levels of the splenocytes in the gamma-ray-irradiated mice. Reduced glutathione exogenously added to splenocytes obtained from normal mice enhanced the proliferative response and NK activity in a dose-dependent manner. The inhibitory effects of radiation on tumor growth was then examined in EST-bearing mice. Repeated low-dose irradiation (0.5 Gy, four times, before and within an early time after inoculation) significantly delayed the tumor growth. Finally, the effect of single low-dose (0.5 Gy), whole-body gamma-ray irradiation on immune balance was examined to elucidate the mechanism underlying the antitumor immunity. The percentage of B cells in blood lymphocytes was selectively decreased after radiation, concomitant with an increase in that of the helper T cell population. The IFN-gamma level in splenocyte culture prepared from EST-bearing mice was significantly increased 48 h after radiation, although the level of IL-4 was unchanged. IL-12 secretion from macrophages was also enhanced by radiation. These results suggest that low-dose gamma-rays induce Th1 polarization and enhance the activities of tumoricidal effector cells, leading to an inhibition of tumor growth.

Animals↗
PubMed1995

Alcohol modulation of immune function: clinical and experimental data. Veterans Affairs Cooperative Study Groups 119 and 275.

In both animal and human studies, ethanol seems to modulate host immune function. In a variety of animal studies, ethanol has been shown to decrease lymphocyte function and number. In human studies of patients with alcoholic hepatitis, these abnormalities were also seen with specific correlation with protein malnutrition. Hepatic pathological lesions were also correlated with lymphocyte subset infiltration. However, peripheral blood lymphocytes did not correlate consistently with hepatic histopathology.

Animals↗
PubMed1998

n-3 polyunsaturated fatty acids and immune function.

n-3 PUFA have been shown to reduce the risk of cardiovascular and inflammatory diseases. However, they have also been shown to suppress T-cell-mediated immune function, an undesirable effect, especially in immuno-suppressed individuals. Studies have thus far suggested that this immuno-suppression may be in part attributable to increased lipid peroxidation and decreased antioxidant (especially vitamin E) levels, which can be prevented by appropriate vitamin E supplementation. Further well-designed human studies are needed to determine the appropriate levels of n-3 PUFA and vitamin E supplementation to optimize the beneficial anti-inflammatory effect of n-3 PUFA and minimize their suppressive effect on T-cell function.

Animals↗