Effect of hydrogenated and saturated, relative to polyunsaturated, fat on immune and inflammatory responses of adults with moderate hypercholesterolemia

Consumption of diets high in hydrogenated fat/trans fatty acids has been shown to have an adverse affect on lipoprotein profiles with respect to cardiovascular disease risk. Dietary fat and cholesterol play an important role in the regulation of immune and inflammatory responses shown to be involved in atherogenesis. We investigated the effects of diets containing hydrogenated fat on cellular immune response and production of inflammatory cytokines in human subjects with moderately elevated cholesterol levels (LDL cholesterol >130 mg/dl). In a double blind cross-over study, 19 subjects consumed three diets, 30% of calories as fat, of which two thirds were provided as soybean oil, soybean oil-based stick margarine, or butter for 32 days, each in a randomized order. Production of proinflammatory mediators, prostaglandin (PG)E(2), interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha); delayed type hypersensitivity (DTH) response, in vitro lymphocyte proliferation, and production of IL-2 were determined. Production of IL-6 and TNF-alpha was significantly higher after consumption of stick margarine diet compared with soybean oil diet. IL-1beta and TNF-alpha production correlated positively with ratios of total cholesterol to HDL cholesterol (r = 0.499, P < 0.001 and r = 0.291, P = 0.04, respectively). There was no significant difference in DTH response, lymphocyte proliferation, or levels of IL-2 and PGE(2) produced among three groups. Our results indicate that consumption of a diet high in hydrogenated fat does not adversely affect cellular immunity but increases production of inflammatory cytokines that have been associated with the pathophysiology of atherosclerosis.     

Relationship between systemic inflammation and delayed-type hypersensitivity response to Candida antigen in older adults

Research has shown that aging is associated with increased systemic inflammation as well as a reduction in the strength of immune responses. However, little evidence exists linking the decrease in cell-mediated immunity in older adults with other health parameters. We sought to examine the relationship between cell-mediated immunity as measured in vivo by the delayed-type hypersensitivity (DTH) response to candida antigen and demographic and physiological variables in older (65-80 y.o.) adults. Candida antigen response was not related to gender or obesity, or to a number of other physiological variables including fitness and body composition. However, positive responders had significantly lower serum C-reactive protein levels (CRP, p<0.05) vs. non-responders. Furthermore, subjects with CRP<4.75 mg?L(-1) had greater odds of developing a positive response compared to those with CRP>4.75 mg?L(-1). Therefore, positive responses to candida antigen in older adults appears to be related to lower levels of systemic inflammation.     

Mycoplasma pulmonis depresses humoral and cell-mediated responses in mice

Humoral and cell-mediated immune responses to sheep red blood cells (SRBC) were studied in mice infected experimentally with Mycoplasma pulmonis. The hemagglutinating (HA) antibody against SRBC was evaluated at 0, 3, 5, 7, 14, 21 and 28 days postinfection (PI). Antibody tiers during all days PI were depressed significantly (p less than 0.05) in infected mice as compared to noninfected controls. The HA antibody, which is of the IgM class, peaks at day 5 PI. There is no shift in the kinetics of the humoral response in M. pulmonis infected mice. Cellular immune responses were evaluated by a delayed-type hypersensitivity (DTH) reaction and the lymphocyte transformation technique. Mice were sensitized at 0,3,5,7,14, 21 and 28 days PI with SRBC and challenged by footpad injection of SRBC 7 days later. The DTH reaction measured at 24 hours after challenge was depressed significantly (p less than 0.05) in all infected animals. After a transient enhancement on day 3 PI, the DTH responses remained depressed through day 28 PI. The lymphocyte transformation test showed a significantly (p less than 0.05) depressed response except on days 5 and 7 PI. These results indicate that M. pulmonis infection in mice suppresses the humoral antibody and cell-mediated immune responses.     

The effect of selenium supplementation on DTH skin responses in healthy North American Men

The trace element selenium (Se) is essential for immune system development and function in animals. However, the exact functions of Se in the human immune system and the achievable health benefits from Se supplementation remain unclear. To test whether an increased intake of dietary Se affects immune function, we conducted a randomized, controlled trial of Se supplementation in healthy free-living men. Forty-two men were administered 300 μg of Se a day as high-Se Baker's yeast, or low-Se yeast for 48 weeks. Serum immunoglobulins, differential complete blood counts and lymphocyte sub-populations were measured every 6 weeks. Tests of delayed-type hypersensitivity (DTH) skin responses to mumps, candida, trychophyton, tuberculin-purified protein, and tetanus were performed at baseline and at the end of 48 weeks of treatment. Supplementation increased blood Se concentration by 50%. Surprisingly, consumption of the low-Se yeast induced anergy in DTH skin responses and increased counts of natural killer (NK) cells and T lymphocytes expressing both subunits of the high affinity interleukin-2 receptor (IL2R). DTH skin responses and IL2R+ cells did not change in the high-Se group, suggesting Se supplementation blocked induction of DTH anergy. There were no differences between groups in quality of life indicators, number of days sick, other leukocyte phenotypes, serum immunoglobulins, or complement factors. These results suggest that Se plays a role in immunotolerization, a cell-mediated process involved in many aspects of immune function.     

Alloantigens placed into the anterior chamber of the eye induce specific suppression of delayed-type hypersensitivity but normal cytotoxic T lymphocyte and helper T lymphocyte responses

Intracameral inoculation of allogeneic B16F10 melanoma cells (C57BL/6) into LP/J mice resulted in progressively growing intraocular tumors and impaired delayed-type hypersensitivity (DTH) reactivity. Additional experiments showed that DTH responses were specifically down-regulated by splenic T suppressor cells. By contrast, subcutaneous inoculation of B16F10 melanoma cells induced significant DTH responses to the alloantigens expressed on the tumor cells and stimulated brisk rejection of the subcutaneously injected tumor cells. In spite of the T suppressor cell inhibition of DTH reactivity, significant cytotoxic T lymphocyte activity could be demonstrated in lymphoid cell suspensions from hosts harboring allogeneic intraocular tumors. The demonstrated cytotoxic T lymphocyte activity is particularly noteworthy because it occurs in the face of severely suppressed DTH responsiveness and thus implies that the intracameral presentation of alloantigens evokes a precise immunoregulatory process that selectively and concomitantly modulates specific cellular immune components; one immune process (cytotoxic T lymphocyte function) is stimulated whereas the other (DTH responsiveness) is down-regulated.     

Concomitant administration of hapten and IL-2-toxin (DAB486-IL-2) results in specific deletion of antigen-activated T cell clones

During the proliferative burst after Ag recognition, T cells express cell-surface, high-affinity IL-2R. The importance of IL-2R+ T cells in supporting/mediating tissue injury has been documented by the ability of mAb anti-IL2R therapies to prevent allograft rejection and autoimmunity. The delayed-type hypersensitivity (DTH) response, an experimental model of T-dependent immunity, offers the possibility of studying responses mounted against defined Ag. We previously reported that the chimeric IL-2 toxin (DAB486-IL-2) prevents DTH responses and selectively eliminates activated IL-2R bearing CD4 and CD8 T cells from lymph nodes draining the site of inflammation. We have examined the duration of immunosuppression and relative specificity of action of DAB486-IL-2 and anti-CD3 mAb for Ag-activated clones in a murine model of DTH using two different noncross-reacting haptens. Treatment with DAB486-IL-2 generates a state of selective unresponsiveness to subsequent challenge with the hapten introduced during the therapeutic period. Immediately after cessation of DAB486-IL-2 therapy, immunization with an unrelated hapten induces a normal vigorous immune response. By comparison, anti-CD3 mAb treatment causes a broad immunosuppression because unrelated haptens introduced after anti-CD3 therapy do not evoke a vigorous immune response. After cessation of DAB486-IL-2 toxin treatment response to the hapten is eventually restored probably by cells trafficking from the thymus, because thymectomized hosts remain unresponsive to the hapten. Taken together these data reinforce the role of the IL-2R as an important target for immunosuppression in T cell-mediated immune reactions. DAB-486-IL-2 treatment confers highly selective immunosuppression.     

Induction of cellular and humoral responses by autoclaved and heat-killed antigen of Leishmania donovani in experimental visceral leishmaniasis

The potential of autoclaved and heat-killed antigen of Leishmania donovani to induce cell-mediated and humoral response has been evaluated in the present study. The vaccines were delivered thrice subcutaneously at an interval of 2 weeks. Two weeks after second booster, BALB/c mice were challenged with 10⁷ stationary phase promastigotes of L. donovani. Significant protection was achieved in immunized mice against L. donovani challenge with 69% to 76% and 59% to 64% reduction in parasite load in the liver and spleen respectively. Immunization induced significantly higher level of delayed type hypersensitivity (DTH) response in mice immunized with heat-killed antigen followed by autoclaved antigen. The immune response was assessed by quantifying Leishmania-specific antibodies and cytokine production. The antibody response was predominantly of IgG type with increased IgG2a production and lesser amount of IgM. The immunization preferentially stimulates the production of IFN-γ and IL-2 in splenocytes which suggests a Th1 type response with a concomitant down-regulation of IL-10 and IL-4. These results indicate a potential for the heat-killed and autoclaved antigen as a vaccine which could trigger cell-mediated immune response.     

Desensitization of delayed-type hypersensitivity in mice: suppressive environment

The systemic injection of high doses of antigen into a preimmunized animal results in transient unresponsiveness of cell-mediated immune responses. This phenomenon is known as desensitization. Serum interleukin 2 (IL-2) activity was found transiently in desensitized mice at 3 h after the antigen challenge. These mice could not reveal antigen nonspecific delayed-type hypersensitivity (DTH) 1 d after the challenge. Specific suppression of DTH was observed at later stages. Sera from 3 h desensitized mice showed suppressive effects on DTH in preo immunized mice. Administration of recombinant IL-2 into preimmunized mice led to the failure of development of DTH to antigens. These observations suggest that IL-2 plays an important role in the suppressive environment.     

Partial IL-10 inhibition of the cell-mediated immune response in chronic beryllium disease.

Chronic beryllium disease (CBD) provides a human disorder in which to study the delayed type IV hypersensitivity response to persistent Ag that leads to noncaseating pulmonary granuloma formation. We hypothesized that, in CBD, failure of IL-10 to modulate the beryllium-specific, cell-mediated immune response would result in persistent, maximal cytokine production and T lymphocyte proliferation, thus contributing to the development of granulomatous lung disease. To test this hypothesis, we used bronchoalveolar lavage cells from control and CBD subjects to evaluate the beryllium salt-specific production of endogenous IL-10 and the effects of exogenous human rIL-10 (rhIL-10) on HLA expression, on the production of IL-2, IFN-gamma, and TNF-alpha, and on T lymphocyte proliferation. Our data demonstrate that beryllium-stimulated bronchoalveolar lavage cells produce IL-10, and the neutralization of endogenous IL-10 does not increase significantly cytokine production, HLA expression, or T lymphocyte proliferation. Second, the addition of excess exogenous rhIL-10 partially inhibited the beryllium-stimulated production of IL-2, IFN-gamma, and TNF-alpha; however, we measured no change in T lymphocyte proliferation or in the percentage of alveolar macrophages expressing HLA-DP. Interestingly, beryllium salts interfered with an IL-10-stimulated decrease in the percentage of alveolar macrophages expressing HLA-DR. We conclude that, in the CBD-derived, beryllium-stimulated cell-mediated immune response, low levels of endogenous IL-10 have no appreciable effect; exogenous rhIL-10 has a limited effect on cytokine production and no effect on T lymphocyte proliferation or HLA expression.     

Effect of dietary tea polyphenols on growth performance and cell-mediated immune response of post-weaning piglets under oxidative stress

To gain insights into the effects of tea polyphenols (TP) on growth performance and cell-mediated immune response of piglets under oxidative stress, an oxidative stress model was established by intraperitoneally injecting weaned piglets with diquat. After intake of either basal diet or TP-supplemented diet for 7 d, half of the piglets in each group were challenged with diquat. Results showed that dietary TP alleviated growth depression to some extent. A T lymphocyte transformation test (LTT) demonstrated that TP promoted the proliferation and activation of T lymphocytes. The ratio of CD4+/CD8+ was elevated, indicating a recovering tendency from immune damages caused by oxidative stress. The increment of pro-inflammatory IL-1 caused by oxidative stress was attenuated, and the concentration of serum IFN-γ was decreased by TP-supplementation. However, the serum concentrations of anti-inflammatory cytokine, such as IL-4, were greatly enhanced by TP, which suggested an immune shift from Th1 to Th2. These findings supported the immunomodulatory potential of TP for piglets subjected to oxidative stress.     

Immunology of Dermatophytosis

The immune response to infection by dermatophytes ranges from a non-specific host mechanism to a humoral and cell-mediated immune response. The currently accepted view is that a cell-mediated immune response is responsible for the control of dermatophytosis. Indeed, some individuals develop a chronic or recurrent infection mediated by the suppression of a cell-mediated immune response. The immune response to Trichophyton is unusual in that this fungus can elicit both immediate hypersensitivity (IH) and delayed-type hypersensitivity (DTH) in different individuals when they are submitted to a skin test reaction. Understanding the nature and function of the immune response to dermatophytes is an exciting challenge that might lead to novel approaches in the treatment and immunological prophylaxis of dermatophytosis.     

Lymphocyte recruitment in delayed-type hypersensitivity. The role of IFN-gamma

Lymphocytes are recruited out of the blood into delayed-type hypersensitivity (DTH) reactions, but the factors controlling their migration are poorly understood. Our previous studies have shown that IFN-alpha/beta, its inducers, and T cell lymphokines can induce lymphocyte migration into the skin after intradermal injection. The present studies were designed to determine the effect of rIFN-gamma, IL-1, and anti-IFN-gamma on lymphocyte recruitment into DTH. Small peritoneal exudate lymphocytes, which preferentially migrate to inflammatory sites, were labelled with 111In and injected i.v. into rats. The intradermal injection of IFN-gamma stimulated the migration of these lymphocytes into the skin. IL-1 induced very little migration by itself, but enhanced the effect of IFN-gamma. Kinetic analysis demonstrated that the migration of lymphocytes to IFN-gamma was rapid, with a peak at 6 h, whereas migration into a DTH reaction was minimal for the first 8 h and reached a peak 24 h after intradermal injection. Polyclonal rabbit anti-IFN-gamma anti-serum, and a Mab to IFN-gamma, DB-2, could almost completely block lymphocyte migration induced by IFN-gamma. Furthermore, DB-2 inhibited lymphocyte recruitment into DTH reactions by 50 to 90%. This Mab did not affect migration in response to IFN-alpha/beta, although it partially inhibited the response to polyI:C. The effect of IFN-gamma on lymphocyte recruitment was not specific for small peritoneal exudate lymphocytes, because both spleen T cells and lymph node cells migrated in response to IFN-gamma and DB-2 inhibited the recruitment of splenic T cells to DTH. Thus, IFN-gamma is a potent stimulator of lymphocyte migration into the skin and a major mediator of lymphocyte recruitment into DTH.     

Infection with Schistosoma mansoni alters Th1/Th2 cytokine responses to a non-parasite antigen.

Schistosoma mansoni infection in the mouse has been shown to be accompanied by a down-regulation in parasite-Ag- and mitogen-induced Th1 cytokine secretion (IL-2 and IFN-gamma) with a simultaneous increase in the production of Th2 cytokines (IL-4, IL-5, and IL-10), suggesting a generalized imbalance in lymphocyte function. In the present study, we examined whether infection with S. mansoni would also influence the character of immune responses to a non-parasite Ag, sperm whale myoglobin (SwMb). When spleen cells (SC) from schistosome-infected SwMb-immunized animals were stimulated with SwMb, their production of IL-2 and IFN-gamma per CD4+ cell was found to be significantly reduced (by 45% and 59%, respectively) compared with the responses observed in immunized uninfected animals. Moreover, SwMb-induced secretion of IL-4 per CD4+ cell was increased threefold in SC cultures from infected mice. No myoglobin-induced IL-5 was detected in the same cultures. Addition to SC cultures of a neutralizing mAb specific for IL-10 partly restored the suppressed IFN-gamma response to SwMb seen in infected mice, suggesting a role for IL-10 in the observed down-regulation. S. mansoni-infected mice also showed an impaired antibody response to SwMb, with levels ranging from 10% to 27% of those observed in uninfected mice, although no differences in IgG isotype were evident. Taken together, these results suggest that infection with S. mansoni induces a down-regulation of Th1 responses and elevation of Th2 responses to unrelated foreign immunogens as well as to parasite Ag themselves. One implication of these findings is that helminth-infected individuals may have altered cell-mediated immune function to other microbial agents.     

Augmentation of cellular immune response by Ipomoea obscura and Ipobscurine alkaloid attenuates tumor growth in mice

The immune status of the host plays a crucial role in controling the process of carcinogenesis. General or selective activation of various immunocompetent cells and their secretory function to maintain a healthy immune status may help in cancer prophylaxis, as well as therapy. The present study focused on the effect of Ipomoea obscura and Ipobscurine on cell-mediated immune response. In this study we evaluated the effect of I.?obscura and an indole alkaloid fraction from I. obscura on effector mechanisms of cell-mediated immune response by analyzing cytotoxic T lymphocyte (CTL) activity, natural killer (NK) cell activity, antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent complement-mediated cytotoxicity (ACC). The effect of I. obscura and Ipobscurine on interleukin-2 (IL-2) and interferon-γ (IFN-γ) levels was also analyzed. In the in vitro and in vivo systems, I. obscura and Ipobscurine treatment augmented cell-mediated immune response by enhancing the killing activity of CTL and NK cells from splenocytes in normal as well as tumor-bearing mice. ADCC and ACC were also enhanced significantly in both normal and tumor-bearing animals after drug administration, compared with untreated control. Administration of I. obscura and Ipobscurine significantly enhanced the production of IL-2 and IFN-γ in normal as well as tumor-bearing animals. This study reveals that both I. obscura and Ipobscurine have the potential to augment immune response through the enhanced secretion of IL-2 and IFN-γ by T cells and thereby inhibit tumor growth and as an alternative medicine for cancer treatment.     

Eosinophil activation and T lymphocyte infiltration in allergen-induced late phase skin reactions and classical delayed-type hypersensitivity.

T lymphocyte infiltration is a well documented feature of classical delayed-type hypersensitivity (DTH) reactions. Recently, we have shown that T lymphocytes and activated (EG2+) eosinophils accumulate in the allergen-induced late phase skin reaction (LPR). To compare the kinetics and phenotypic composition of these T lymphocyte responses, LPR and DTH reactions of comparable induration size were induced in atopic subjects. In addition, DTH and LPR were compared between atopic and nonatopic subjects. In atopic individuals, allergen challenge elicited a perivascular influx of T lymphocytes that was predominantly CD4+. Eosinophil accumulation and activation were also prominent. There was no cellular response to allergen challenge in the nonatropic group. In both groups, DTH responses showed an intense T cell infiltrate which was more dense and dispersed than in the LPR. CD4+ T cells predominated but at 48 h CD8+ numbers were also significantly increased. In DTH, total leukocyte numbers (CD45+) were increasing at 48 h, whereas in the LPR, cell numbers reached a plateau between 24 and 48 h. T cell activation (shown by expression of IL-2R) was more prominent in DTH. Endothelial expression of HLA-DR was increased in both LPR and DTH, implying the local release of inflammatory cytokines in both reactions. Small but significant numbers of activated eosinophils (EG2+) were detected in atopics and non-atopics at 24 h in DTH but not at 48 h. These findings suggest that the allergen-induced LPR induced in atopic subjects is, at least in part, a form of cell-mediated hypersensitivity but with T cell kinetics that differ from classical DTH.     

Effect of fish oil diet on immune response and proteinuria in mice

In this study, we examined the immune response and proteinuria caused by dietary polyunsaturated fatty acids in normal NZW/N and autoimmune NZB/NZW mice. Mice were maintained more than one year on five dietary groups: normal (5% corn oil), calorie-restricted, high fat (20% corn oil), high fat (20% fish oil), and Purina laboratory rodent chow. Normal mice fed with the fish oil diet had a more reduced anti-sheep red blood cells (SRBC) plaque-forming cell (PFC) response and less interleukin-2 (IL-2) enhancement of PFC than did the group with the restricted diet and the young control group. The corn oil (5 and 20%) diet animals also showed reduced PFC response and IL-2 utilization. NZB/NZW mice fed with the fish oil diet showed similar reduced PFC response but had a significantly lower response to IL-2 than did those on the corn oil diets and the restricted diet. The IL-2 production by macrophages from NZW/N mice was reduced in both the fish oil and corn oil diet groups. However, mice fed with the fish oil diet had less proteinuria and good survival rates, similar to the group with the restricted diet. These results suggest that the beneficial effect of the fish oil diet in these animals may be attributed in part to the immunosuppression mechanism.     

Contrasting effects of acute and chronic gastro-intestinal helminth infections on a heterologous immune response in a transgenic adoptive transfer model

We have previously found that co-immunisation with ovalbumin (OVA) and the body fluid of the helminth Ascaris suum inhibited an OVA-specific delayed type hypersensitivity (DTH) response by reducing OVA-specific CD4+ T lymphocyte proliferation via an IL-4 independent mechanism. In the present study, we determined whether parasite infections themselves could induce similar changes to peripheral immunisation by examining the modulation of OVA-specific immune responses during acute and chronic helminth infections. Surprisingly, an acute infection with Trichinella spiralis, but not a chronic infection with Heligmosomoides polygyrus, inhibited the OVA-specific DTH reaction. Correspondingly, the T helper 1 (Th1) OVA-specific response was decreased in mice infected with T. spiralis, but not with H. polygyrus. Inhibition of the Th1 response may be a result of a shift in the Th1/Th2 balance as although both H. polygyrus and T. spiralis infected mice induced a Th2 OVA-specific response, that exhibited by T. spiralis was more potent. Furthermore, although IL-10 secretion upon OVA restimulation was similarly increased by both infections, production of this immunoregulatory cytokine may play a role in the suppression of immune responses observed with T. spiralis infection depending on the context of its release. Interestingly, analysis of the OVA-specific T lymphocyte division by carboxyfluorescein diacetate succinimidyl ester (CFSE) staining revealed that gastro-intestinal infection with the acute helminth T. spiralis, but not with chronic H. polygyrus, inhibited the systemic immune response by significantly inhibiting the antigen-specific T cell proliferation during the primary response, a mechanism similar to that observed when A. suum parasite extracts were directly mixed with the OVA during immunisation in our previous studies.     

Maternal Diet Supplemented with Methyl-Donors Protects against Atherosclerosis in F1 ApoE?/? Mice

Atherosclerosis is an inflammatory condition of the arterial wall mediated by cells of both innate and adaptive immunity. T lymphocytes play an important role in orchestrating the pathogenic immune response involved in the acceleration of atherosclerosis. Previously, we have shown that a prenatal methyl-donor supplementation diet (MS), when fed to dams during pregnancy and lactation, decreased the T cell-mediated pro-inflammatory cytokine and chemokine response in F1 mice. In the current study, we report feeding Apolipoprotein E (ApoE^−/−) deficient dams with the MS diet during pregnancy reduces atherosclerotic plaques in F1 mice that were fed high fat diet (HFD) after weaning. F1 mice from dams on the MS diet exhibited increased global T cell DNA methylation. T-cell chemokines and their receptors (in particular CCR2, CCR5, and CXCR3) play important roles in the inflammatory cell recruitment to vascular lesions. MS diet significantly reduced Ccr2 mRNA and protein expression in CD3+ T cells but not in CD11b+ monocytes in MS F1 mice relative to controls. F1 litter size, HFD consumption, body weight, and body fat were similar between control and MS diet groups. Moreover, serum thiol metabolite levels were similar between the two groups. However, MS diet is associated with significantly higher serum HDL and lower LDL+VLDL levels in comparison to F1 mice from dams on the control diet. Inflammatory cytokines (IL-17, TNF-α, IL-6) were also lower in MS F1 mice serum and conditioned media from T-cell culture. Altogether, these data suggest that the MS diet ameliorates development of atherosclerosis by inhibiting the T-cell Ccr2 expression, reducing inflammatory cytokines production and increasing serum HDL:LDL ratio.     

T cell responses are better correlates of vaccine protection in the elderly

It is commonly held that increased risk of influenza in the elderly is due to a decline in the Ab response to influenza vaccination. This study prospectively evaluated the relationship between the development of influenza illness, and serum Ab titers and ex vivo cellular immune responses to influenza vaccination in community dwelling older adults including those with congestive heart failure (CHF). Adults age 60 years and older (90 subjects), and 10 healthy young adult controls received the 2003-04 trivalent inactivated influenza vaccine. Laboratory diagnosed influenza (LDI) was documented in 9 of 90 older adults. Pre- and postvaccination Ab titers did not distinguish between subjects who would subsequently develop influenza illness (LDI subjects) and those who would not (non-LDI subjects). In contrast, PBMC restimulated ex vivo with live influenza virus preparations showed statistically significant differences between LDI and non-LDI subjects. The mean IFN-gamma:IL-10 ratio in influenza A/H3N2-stimulated PBMC was 10-fold lower in LDI vs non-LDI subjects. Pre-and postvaccination granzyme B levels were significantly lower in CHF subjects with LDI compared with subjects without LDI. In non-CHF subjects with LDI, granzyme B levels increased to high levels at the time of influenza infection. In conclusion, measures of the ex vivo cellular immune response to influenza are correlated with protection against influenza while serum Ab responses may be limited as a sole measure of vaccine efficacy in older people. Ex vivo measures of the cell-mediated immune response should be incorporated into evaluation of new vaccines for older adults.     

Leishmania donovani Infection of a Susceptible Host Results in Apoptosis of Th1-Like Cells: Rescue of Anti-Leishmanial CMI by Providing Th1-Specific Bystander Costimulation

A protective immune response against Leishmania donovani infection is mediated by T-helper type 1 (Th1) cells. Th1 induced cell-mediated immunity (CMI), as assessed by anti-leishmanial DTH response, is lost in a susceptible host such as BALB/c mice. Although the impaired Th1 function eventuates in unhindered parasite growth and in manifestation of the susceptible phenotype, the mechanism of down-regulation of the Th1 function is yet to be elucidated. Here, we provide evidence that the parasite downregulates the expression of a Th1-specific costimulatory molecule, M150, on the surface of infected BALB/c mice-derived macrophages. Th cells are rendered unresponsive to anti-CD3 Ab-mediated stimulation after interaction with infected macrophages. The anergized T cells produce much less IL-2, IL-4 and IFN-γ compared to those T cells which were costimulated using normal macrophages. The defect in proliferation, anti-CD3 Ab induced unresponsiveness and IFN-γ but not IL-4 production can be restored by providing bystander costimulation through M150. These results not only unfold a novel immune evasion strategy used by the parasite but also clarify the mechanism of Th1 cell debilitation during the disease. Recovery of Th1 cytokine production by bystander costimulation through M150 may help in formulating a new strategy for the elimination of intracellular parasites.