Cutaneous Delayed-type Hypersensitivity Responses Research Articles

Individual and sociodemographic factors associated with polysensitization at a New York City hospital

Allergic contact dermatitis (ACD) is a cutaneous delayed-type hypersensitivity response with a global prevalence estimated at over 20%.1 The gold standard for diagnosis is patch testing, in which allergens are applied to a patient's skin to elicit cutaneous responses in sensitized individuals. Many patients undergoing patch testing test positive for 3 or more unrelated allergens, termed polysensitization.2 A recent North American Contact Dermatitis Group study found that 32.1% of patients tested were positive to at least three allergens, but reported rates vary.3

Nadroparin carries a potentially high risk of inducing cutaneous delayed-type hypersensitivity responses.

Heparins are widely used for the prophylaxis/treatment of thromboembolic events. As adverse effects, heparin-induced skin lesions occur frequently (in 7.5-39% of patients). Skin lesions may be the only clinical manifestation of life-threatening immune-mediated heparin-induced thrombocytopenia, but are commonly caused by a delayed-type hypersensitivity response [heparin-induced delayed-type hypersensitivity (HIHS)]. Risk factors have not been prospectively identified. To identify possible risk factors for heparin-induced skin lesions from three independent clinical trials in a combined analysis. A pooled analysis from prospective studies was performed, and possible risk factors were included in a multiple logistic regression analysis. Obesity (body mass index of > 25), prolonged anticoagulant therapy, prior heparin exposure and younger age (< 55 years) were confirmed as independent risk factors for HIHS. The choice of anticoagulant preparation had the greatest influence. On comparison of dalteparin, enoxaparin, fondaparinux, unfractionated heparin, and nadroparin, the latter was associated with the highest risk of eliciting HIHS (odds ratio of 30.2, 95%CI: 11.7-77.9). The high risk associated with nadroparin has been validated in controlled trials, and this emphasizes the singularity of each heparin preparation in terms of allergenicity and that individualized anticoagulation is required.

Histopathological Characterization of Cutaneous Delayed-type Hypersensitivity and Correlations with Intestinal Pathology and Systemic Immune Responses in Sheep with Paratuberculosis

Cell-mediated immunity has been exploited historically in the diagnosis of mycobacterial diseases through elicitation of a delayed-type hypersensitivity (DTH) reaction following intradermal injection of an antigen. Here we describe the histopathological features of the cutaneous DTH reaction and its association with intestinal pathology and systemic immune responses in sheep with Mycobacterium avium subspecies paratuberculosis (MAP) infection. A mixed mononuclear cellular infiltrate dominated the DTH reaction and was present in perivascular and periadnexal patterns. Multiple multinucleate giant cells were present in the cellular infiltrate in one sheep while plasma cells were an obvious feature in six others. Sheep with paucibacillary intestinal lesions had the greatest degrees of cutaneous induration, more severe cellular infiltration in DTH lesions and high systemic interferon (IFN)-γ production. In contrast, sheep with multibacillary intestinal lesions, and particularly those with dissemination of MAP to extra-intestinal tissues, had minimal cutaneous induration, nil to mild cellular infiltration in DTH lesions and high serum anti-MAP antibody levels. Systemic IFN-γ production generally was augmented following skin sensitization. In general, the gross and histopathological features of the cutaneous DTH response matched the stage of paratuberculosis reflected by intestinal pathology and systemic measures of humoral and cellular immunity.

A Microbial Glycolipid Functions as a New Class of Target Antigen for Delayed-type Hypersensitivity

Delayed-type hypersensitivity (DTH) is marked by high levels of protein antigen-specific T cell responses in sensitized individuals. Recent evidence has revealed a distinct pathway for T cell immunity directed against glycolipid antigens, but DTH to this class of antigen has been undetermined and difficult to prove due to their insolubility in aqueous solutions. Here, glucose monomycolate (GMM), a highly hydrophobic glycolipid of the cell wall of mycobacteria, was dispersed in aqueous solutions in the form of octaarginine-modified liposomes and tested for its ability to elicit cutaneous DTH responses in bacillus Calmette-Guerin (BCG)-immunized guinea pigs. After an intradermal challenge with the GMM liposome, a significant skin induration was observed in BCG-immunized, but not mock-treated, animals. The skin reaction peaked at around 2 days with local infiltration by mononuclear cells, and therefore, the response shared basic features with the classical DTH to protein antigens. Lymph node T cells from BCG-immunized guinea pigs specifically increased IFN-γ transcription in response to the GMM liposome, and this response was completely blocked by antibodies to CD1 lipid antigen-presenting molecules. Finally, whereas the T cells increased transcription of both T helper (Th) 1-type (IFN-γ and TNF-α) and Th2-type (IL-5 and IL-10) cytokines in response to the purified protein derivative or tuberculin, their GMM-specific response was skewed to Th1-type cytokine production known to be critical for protection against tuberculosis. Thus, our study reveals a novel form of DTH with medical implications.

Concordance of CCR5 Genotypes that Influence Cell-Mediated Immunity and HIV-1 Disease Progression Rates

We used cutaneous delayed-type hypersensitivity responses, a powerful in vivo measure of cell-mediated immunity, to evaluate the relationships among cell-mediated immunity, AIDS, and polymorphisms in CCR5, the HIV-1 coreceptor. There was high concordance between CCR5 polymorphisms and haplotype pairs that influenced delayed-type hypersensitivity responses in healthy persons and HIV disease progression. In the cohorts examined, CCR5 genotypes containing -2459G/G (HHA/HHA, HHA/HHC, HHC/HHC) or -2459A/A (HHE/HHE) associated with salutary or detrimental delayed-type hypersensitivity and AIDS phenotypes, respectively. Accordingly, the CCR5-Δ32 allele, when paired with non-Δ32-bearing haplotypes that correlate with low (HHA, HHC) versus high (HHE) CCR5 transcriptional activity, associates with disease retardation or acceleration, respectively. Thus, the associations of CCR5-Δ32 heterozygosity partly reflect the effect of the non-▵32 haplotype in a background of CCR5 haploinsufficiency. The correlations of increased delayed-type hypersensitivity with -2459G/G-containing CCR5 genotypes, reduced CCR5 expression, decreased viral replication, and disease retardation suggest that CCR5 may influence HIV infection and AIDS, at least in part, through effects on cell-mediated immunity.

Tapering immunosuppressive therapy significantly improves in vivo cutaneous delayed type hypersensitivity responses

Immunosuppressive therapy affects cell-mediated immunity and thereby increases the frequency of infections and malignancies in transplanted patients. We questioned whether reducing the immunosuppressive dose in stable kidney transplant patients has an in vivo effect on cutaneous delayed type hypersensitivity responses (DTH) reflecting cell-mediated immunity. We measured DTH responses to recall antigens (Tetanus, Diphteria, Streptococcus, Tuberculin, Candida, Trychophyton, Proteus, glycerin control) on the volar surface of the forearm in patients before and after successful reduction (50%) of the dose of mycophenolate mofetil (MMF) or azathioprine (AZA). In addition, we tested healthy individuals who were age- and sex-matched to the patient group. Results of the skin reaction test were calculated as the sum in millimeters (mm) of all positive reactions (score), and as the number of positive antigens. Patients treated with a high dose of MMF or AZA had a significantly lower test score compared to healthy controls ( p = 0.01). Also the number of positive antigens was reduced in patients compared to healthy controls ( p = 0.02). After reduction of the MMF or AZA dose, the test score and the number of positive antigens increased significantly ( p = 0.02, p = 0.01, respectively) to comparable scores of healthy controls. Additionally, the mycophenolic acid (MPA) trough level was negatively correlated with the test score ( p = 0.006) and number of positive antigens ( p = 0.004). In conclusion, successful tapering of the MMF or AZA dose in kidney transplant patients more than 2 years after transplantation favorably affects the in vivo DTH response, reflecting an improvement of the general immunity, facilitating the defense against infection and malignancies.

High Growth Rate Fails to Enhance Adaptive Immune Responses of Neonatal Calves and Is Associated with Reduced Lymphocyte Viability

The objective of the study was to evaluate the effects of 3 targeted growth rates on adaptive (i.e., antigen-specific) immune responses of preruminant, milk replacer-fed calves. Calves (9.1±2.4 d of age) were assigned randomly to one of 3 dietary treatments to achieve 3 targeted daily rates of gain [no growth (maintenance) = 0.0kg/d, low growth = 0.55kg/d, or high growth = 1.2kg/d] over an 8-wk period. The NRC Nutrient Requirements of Dairy Cattle calf model computer program was used to estimate the milk replacer intakes needed to achieve target growth rates. All calves were fed a 30% crude protein, 20% fat, all-milk protein milk replacer reconstituted to 14% dry matter. Diets were formulated to ensure that protein would not be limiting. All calves were vaccinated 3wk after initiation of dietary treatments with Mycobacterium bovis, strain bacillus Calmette-Guerin and ovalbumin. Growth rates for no-growth (0.11kg/d), low-growth (0.58kg/d), and high-growth (1.16kg/d) calves differed throughout the experimental period. Blood glucose concentrations in high-growth calves increased with time and were higher than in low- and no-growth calves. Mononuclear and polymorphonuclear leukocyte percentages in peripheral blood were unaffected by growth rate but did change with advancing age. Percentages of CD4+ T cells increased with age in no-growth and low-growth calves, a characteristic of maturation, but failed to increase in high-growth calves. Growth rate did not affect the percentages of CD45RO+ (memory) CD4+ and CD8+ T cells, antigen (i.e., ovalbumin)-specific serum IgG concentrations, or antigen (i.e., purified protein derivative)-induced IFN-γ and nitric oxide secretion by mononuclear cell cultures. Antigen-elicited cutaneous delayed-type hypersensitivity responses of no-growth calves exceeded responses of low-growth, but not high-growth, calves. In resting- and antigen-stimulated cell cultures, viabilities of CD4+, CD8+, and γδTCR+ T cells from high-growth calves were lower than those of the same T cell subsets from no-growth and low-growth calves. Alternatively, resting cultures of mononuclear leukocytes from high-growth calves produced more nitric oxide than those from no-growth and low-growth calves. In conclusion, adaptive immune responses were affected minimally by growth rate. The results suggest that protein-energy malnutrition in the absence of weight loss is not detrimental to antigen-specific responses of neonatal vaccinated calves and that a high growth rate does not enhance these responses. The negative effect of a high growth rate on the viability of circulating T cell populations may influence infectious disease resistance of the calf.

Extraordinarily few organisms of a live recombinant BCG vaccine against tuberculosis induce maximal cell-mediated and protective immunity

In previous studies, we have described a live recombinant BCG vaccine (rBCG30) overexpressing the 30 kDa major secretory protein of Mycobacterium tuberculosis that induces greater protective immunity against tuberculosis than the current vaccine in the demanding guinea pig model of pulmonary tuberculosis. In this study, we have investigated the impact of vaccine dose on the development of cell-mediated and protective immunity in the guinea pig model. We found that the protective efficacy against M. tuberculosis aerosol challenge of both BCG and rBCG30 was essentially dose-independent over a dose range of 10 1–10 6 live organisms. As previously observed, rBCG30 was more potent, reducing colony-forming units (CFU) below the level observed in animals immunized with the parental BCG vaccine by 0.7 logs in the lungs and 1.0 logs in the spleen ( P < 0.0001). To gain a better understanding of the influence of dose on bacterial clearance and immunity, we assessed animals immunized with 10 1, 10 3, or 10 6 CFU of rBCG30. The higher the dose, the higher the peak CFU level achieved in animal organs. However, whereas humoral immune responses to the 30 kDa protein reflected the disparate CFU levels, cell-mediated immune responses did not; high and low doses of rBCG30 ultimately induced comparable peak lymphocyte proliferative responses and cutaneous delayed-type hypersensitivity responses to the 30 kDa protein. We estimate that the amount of the 30 kDa protein required to induce a strong cell-mediated immune response when delivered via 10 rBCG30 organisms is about 9 orders of magnitude less than that required when the protein is delivered in a conventional protein/adjuvant vaccine. This study demonstrates that a very low inoculum of rBCG30 organisms has the capacity to induce strong protective immunity against tuberculosis and that rBCG30 is an extremely potent delivery system for mycobacterial antigens.

Induction of Anti-inflammatory and Altered T-Cell Proliferative Responses by the Ethanol Root Extract of Plumbago zeylanica. in Adjuvant-Induced Arthritic Rats

ABSTRACTThe ethanol root extract of Plumbago zeylanica. L. (PZE) was investigated for anti-inflammatory activity in adjuvant-induced arthritic (AIA) rats. The AIA rats were treated with PZE (20 mg/kg body weight) daily from day 0 to day 13. The PZE reduced the paw thickness and paw volume of AIA rats. The effect of PZE treatment was assessed in cutaneous delayed type hypersensitivity (DTH) response to Mycobacterium. tuberculin (MT) in development of AIA. The results demonstrated that PZE inhibited the development of cutaneous DTH response in AIA rats. The T-cell proliferation induced by concanavalin A (Con A), a mitogen, was depressed in three different strains of AIA rats (Wistar, Lewis, and Fischer) when compared with that of normal; however, the PZE treatment of AIA rats reversed the decrease of T-cell proliferation to the normal levels. The treatment of AIA rats with PZE on splenic T-cell proliferation was also compared with T-cell proliferation of rats that were treated with the known anti-inflammatory compounds such as cyclophosphamide and indomethacin.

Does genotype mask the relationship between psychological factors and immune function?

This paper examined the interaction between genetic influences of the polymorphic human leukocyte antigens (DRB1 and DQB1) and psychological distress on the development of cellular immunity to the novel antigen, keyhole limpet hemocyanin (KLH). Participants ( n = 227) were immunized with KLH and the development of cutaneous delayed-type hypersensitivity (DTH) against KLH was examined 3 weeks later. Distress was assessed using the Profile of Mood States. DNA was typed for the serologically defined DRB1 and DQB1 antigens. There was a significant correlation between distress at immunization and the development of DTH skin test responses to KLH ( n = 214, r = .24, p = .003). HLA DQ2 was weakly associated with a decreased likelihood of developing a cutaneous delayed-type hypersensitivity response against KLH (odds ratio [OR] = 1.6; confidence interval [CI] 0.9–2.7). HLA DQ5 was weakly associated with an increased likelihood of responding to the antigen (OR = 0.6; CI = 0.3–1.0). The correlation between distress and immune function in HLA DQ2 negative individuals was .34 ( n = 136, p = .00) and in HLA DQ2 positive individuals it was .06 ( n = 74, p = .64). For HLA DQ5 negative individuals the correlation was .26 ( n = 140, p = .00) and for HLA DQ5 positive individuals it was .22 ( n = 70, p = .07). These results suggest that the distress/immune relationship in genetically susceptible or protected individuals may be underestimated in psychoneuroimmunology research.

Distinct innate and acquired immune responses to Leishmania in putative susceptible and resistant human populations endemically exposed to L. (Viannia) panamensis infection.

Mechanisms of constitutive and acquired susceptibility/resistance to Leishmania Viannia panamensis (L. (V ) p.) were investigated in endemically exposed human populations presenting either recurrent disease (putative susceptible) or subclinical infection (clinically resistant). Cutaneous delayed type hypersensitivity response to leishmanin was significantly lower among individuals experiencing recurrent leishmaniasis than among those whose skin test converted without developing the disease. Monocyte derived macrophages from individuals with recurrent disease were more permissive in vitro to the entry of parasites than macrophages from subclinically infected individuals. In vitro proliferation of CD4 and CD8 T lymphocytes in response to intracellular amastigotes was significantly lower among individuals with a history of recurrent disease compared with subclinically infected individuals. Linear regression analyses revealed a strong direct relationship between the production of interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-10 by peripheral blood mononuclear cells (PBMC) from resistant (subclinically infected) individuals and no correlation in the production of these cytokines by PBMC from individuals who experienced recurrent disease. The results provide evidence of differences in the innate and acquired responses to Leishmania according to the outcome of the natural infection. These findings support the feasibility of identifying the immunological bases of innate and acquired resistance through studies in naturally exposed human populations.

Mechanisms involved in protective immune response generated by secretory proteins of Mycobacterium habana against experimental tuberculosis.

Live mycobacteria secrete a number of unique proteins early in their multiplication which are important for both the pathogenesis and the stimulation of specific host responses. We have investigated the mechanisms by which the host mounts immune response against tuberculosis after vaccination with secretory proteins (SP) of a vaccine candidate Mycobacterium habana TMC 5135. Mice vaccinated with SP of 10th day growth of M. habana, either alone or emulsified in Freund's incomplete adjuvant (FIA) possessed antituberculous resistance and cellular immune responses against M. tuberculosis H37Rv. These proteins induced a significant cutaneous delayed type hypersensitivity response in guinea pigs vaccinated with heat killed M. tuberculosis H37Rv, which was equivalent to that observed with a standard purified protein derivative (PPD). The splenocytes of these guinea pigs have shown higher proliferative response after stimulation with SP than with PPD. The SP + FIA immunization has been found to exert maximum prophylactic effect by potentiating both the oxygen dependent arms and enzymatic activities of macrophages. Macrophages from mice vaccinated with SP of M. habana produced enhanced levels of interleukin(IL)-2, interleukin-12 and interferon(IFN)-gamma. The protective as well as cell mediated immune responses were upregulated in SP immunized animals when compared to whole cell (M. habana) vaccinated animals. SDS-PAGE of SP from M. habana showed the prominent bands of 60, 32, 31 and 30 kDa. Furthermore, the western analysis of SP with pulmonary tuberculosis patient's serum has revealed the presence of immunoreactive antigens of 36, 35, 33/32 kDa. Overall study demonstrated that the secretory antigens released by actively growing M. habana bacilli could activate different arms of effective immune response.

Interferon-gamma is necessary for initiating the acute rejection of major histocompatibility complex class II-disparate skin allografts.

Although interferon (IFN)gamma has immunostimulatory functions, it is not essential for the acute rejection of fully allogeneic grafts in mice. It is not known whether IFNgamma plays a critical role in the acute rejection of MHC class I- or MHC class II-disparate allografts. We studied the survival of skin allografts transplanted from fully allogeneic (BALB/c), MHC class I-disparate (bml), or MHC class II-disparate (bm12) donors to C57BL/6 wild-type (IFNgamma+/+) and IFNgamma gene-knockout (IFNgamma-/-) recipients. We also investigated the in vitro responses of IFNgamma+/+ and IFNgamma-/- T cells to MHC class II-disparate splenocytes. We found that IFNgamma-/- recipients reject BALB/c and bml skin grafts at the same rate as IFNgamma+/+ mice but are not capable of rejecting bm12 skin. Despite the inability of IFNgamma-/- mice to reject bm12 skin grafts, IFNgamma-/- T cells displayed vigorous proliferation and cytotoxic responses when stimulated with bm12 splenocytes in vitro. Furthermore, priming IFNgamma-/- recipients with bm12 splenocytes enabled these mice to reject bm12 skin grafts at a normal rate and to mount a cutaneous delayed-type hypersensitivity response to the bm12 antigen. The data demonstrate that IFNgamma is not necessary for generating effector mechanisms associated with acute transplant rejection but that it is required for initiating alloimmune responses to MHC class II-disparate skin grafts.

Stress-induced enhancement of cell-mediated immunity.

We have demonstrated that acute stress induces a large-magnitude, rapid, and reversible redistribution of leukocytes from the blood to other compartments within the body. These changes in leukocyte distribution are mediated by adrenal stress hormones. Because the skin is one of the target organs of a stress-induced redistribution of leukocyes, we hypothesized that such a leukocyte redistribution could be one of the factors by which acute stress may enhance cutaneous immune function. This hypothesis was tested by examining the effects of acute stress on cutaneous delayed-type hypersensitivity (DTH). DTH reactions are antigen-specific, cell-mediated immune responses that, depending on the antigen involved, mediate beneficial (resistance to viruses, bacteria, and fungi) or harmful (allergic dermatitis, autoimmunity) aspects of immune function. DTH was induced by challenging the pinnae of previously sensitized rats with 2,4-dinitro-1-fluorobenzene (DNFB). Experiments showed that acute stress administered immediately before the introduction of an antigenic challenge significantly enhances a cutaneous DTH response. In contrast, chronic stress suppresses cutaneous DTH. These results demonstrate a bidirectional relationship between stress and immune function, such that acute stress enhances, while chronic stress suppresses, an important class of immune responses in vivo. They also suggest that stress-induced alterations in lymphocyte redeployment within the body may play an important role in mediating these bidirectional effects of stress on cell-mediated immunity.

Cutaneous delayed-type hypersensitivity response is inhibited in transgenic mice with keratinocyte-specific CD44 expression defect

Cutaneous delayed-type hypersensitivity response is inhibited in transgenic mice with keratinocyte-specific CD44 expression defect

In Vitro Cellular and Cytokine Responses to Mycobacterial Antigens: Application to Diagnosis of Tuberculosis Infection and Assessment of Response to Mycobacterial Vaccines

AbstractMycobacterial infection leads to the development of specific cell-mediated immune responses that have been measured clinically by assessing delayed-type hypersensitivity with Mantoux skin testing. Several characteristics of Mantoux skin testing for tuberculosis infection can make the procedure inaccurate, inconvenient, and sometimes misleading. 1t is also a poor predictor of immunity to tuberculosis in bacille Calmette-Guerin vaccinees, yet decisions to revaccinate often are based on skin test responses after initial immunization. Skin testing with other mycobacterial antigens has similar limitations. In vitro assessment of cellular immunity to mycobacteria offers multiple, potential advantages over skin testing and has become technically feasible in recent years. Measurement of the effector functions that comprise cell-mediated immunity (eg, cytokine secretion and cytotoxicity) rather than cutaneous delayed-type hypersensitivity responses is more likely to reflect meaningfully specific mycobacterial immunity and, therefore, provide a means for determining mycobacterial immunity after immunization. Eliminating the variability in placement and interpretation inherent in skin testing could provide a more stable foundation for comparative studies in populations and improve decision making for individuals. Finally, in vitro testing permits the use of discrete mycobacterial antigens instead of crude protein preparations, allowing greater specificity in the detection of infection as well as assessment of responses to defined candidate vaccine antigens. Several studies have compared skin testing with in vitro proliferation of lymphocytes stimulated by mycobacterial antigens for the detection of Mycobacterium tuberculosis infection. Preliminary veterinary and human studies suggest that in vitro assessment of y-interferon production in response to mycobacterial antigens can be used to detect prior infection with organisms of the M tuberculosis complex. Streamlined techniques for in vitro testing of cellular immunity may allow its practical adoption in the clinical setting and lead to its use as a replacement for Mantoux skin testing.

In vitro cellular and cytokine responses to mycobacterial antigens: application to diagnosis of tuberculosis infection and assessment of response to mycobacterial vaccines.

Mycobacterial infection leads to the development of specific cell-mediated immune responses that have been measured clinically by assessing delayed-type hypersensitivity with Mantoux skin testing. Several characteristics of Mantoux skin testing for tuberculosis infection can make the procedure inaccurate, inconvenient, and sometimes misleading. It is also a poor predictor of immunity to tuberculosis in bacille Calmette-Gúerin vaccinees, yet decisions to revaccinate often are based on skin test responses after initial immunization. Skin testing with other mycobacterial antigens has similar limitations. In vitro assessment of cellular immunity to mycobacteria offers multiple, potential advantages over skin testing and has become technically feasible in recent years. Measurement of the effector functions that comprise cell-mediated immunity (eg, cytokine secretion and cytotoxicity) rather than cutaneous delayed-type hypersensitivity responses is more likely to reflect meaningfully specific mycobacterial immunity and, therefore, provide a means for determining mycobacterial immunity after immunization. Eliminating the variability in placement and interpretation inherent in skin testing could provide a more stable foundation for comparative studies in populations and improve decision making for individuals. Finally, in vitro testing permits the use of discrete mycobacterial antigens instead of crude protein preparations, allowing greater specificity in the detection of infection as well as assessment of responses to defined candidate vaccine antigens. Several studies have compared skin testing with in vitro proliferation of lymphocytes stimulated by mycobacterial antigens for the detection of Mycobacterium tuberculosis infection. Preliminary veterinary and human studies suggest that in vitro assessment of gamma-interferon production in response to mycobacterial antigens can be used to detect prior infection with organisms of the M tuberculosis complex. Streamlined techniques for in vitro testing of cellular immunity may allow its practical adoption in the clinical setting and lead to its use as a replacement for Mantoux skin testing.

Antarctic isolation: immune and viral studies.

Stressful environmental conditions are a major determinant of immune reactivity. This effect is pronounced in Australian National Antarctic Research Expedition populations exposed to prolonged periods of isolation in the Antarctic. Alterations of T cell function, including depression of cutaneous delayed-type hypersensitivity responses and a peak 48.9% reduction of T cell proliferation to the mitogen phytohaemagglutinin, were documented during a 9-month period of isolation. T cell dysfunction was mediated by changes within the peripheral blood mononuclear cell compartment, including a paradoxical atypical monocytosis associated with altered production of inflammatory cytokines. There was a striking reduction in the production by peripheral blood mononuclear cells of the predominant pro-inflammatory monokine TNF-alpha and changes were also detected in the production of IL-1, IL-2, IL-6, IL-1ra and IL-10. Prolonged Antarctic isolation is also associated with altered latent herpesvirus homeostasis, including increased herpesvirus shedding and expansion of the polyclonal latent Epstein-Barr virus-infected B cell population. These findings have important long-term health implications.

Th1 responsiveness to nephritogenic antigens determines susceptibility to crescentic glomerulonephritis in mice

The pattern of glomerulonephritis (GN) developing in response to a planted antigen (sheep anti-mouse GBM globulin) was compared in two strains of mice which demonstrated either a predominant Th1 (C57BL/6) or Th2 (BALB/c) response to this antigen. GN was induced with a subnephritogenic i.v. dose of sheep anti-mouse GBM globulin in mice presensitized to sheep globulin. Sensitized C57BL/6 mice showed pronounced cutaneous delayed-type hypersensitivity (DTH) following the challenge with sheep globulin, low titers of circulating anti-sheep globulin antibody and high interferon gamma (IFN-gamma) and low interleukin 4 (IL-4) production by splenic T cells, consistent with a predominant Th1 pattern of immune response. Sensitized BALB/c mice did not develop DTH following cutaneous challenge with sheep globulin, had higher circulating anti-sheep globulin antibody titers, and showed high IL-4 and low IFN gamma production by splenic T cells compared with C57BL/6 mice, consistent with a predominant Th2 response. In C57BL/6 mice, GN developing in response to sheep globulin exhibited a severe crescentic pattern with prominent glomerular T cell and macrophage influx and fibrin deposition. In vivo depletion with a monoclonal anti-CD4 antibody demonstrated that this injury was T helper cell dependent. Treatment with monoclonal anti-mouse IFN gamma antibody significantly reduced glomerular injury and crescent formation and attenuated the cutaneous DTH response. GN induced by the same protocol in BALB/c mice exhibited pronounced glomerular IgG and complement deposition. Crescent formation, fibrin deposition, and glomerular T cell and macrophage infiltration were significantly less than observed in C57BL/6 mice, and injury was not T cell dependent in the effector phase. These data suggest that the pattern of glomerular injury induced by a planted antigen can be determined by the balance of T helper cell subset activation. A Th1 response induces a severe crescentic pattern of GN, which like cutaneous DTH, is T helper cell and IFN gamma dependent.

Cellular immune responses to recombinant heat shock protein 70 from Histoplasma capsulatum.

Heat shock protein (hsp) 70 from several microbes is antigenic in mammals. In this study we sequenced and expressed the gene encoding this protein from Histoplasma capsulatum to study its immunological activity. The deduced amino acid sequence of the gene demonstrated 71 and 76% identity to hsp7O from humans and Saccharomyces cerevisiae, respectively. A cDNA was synthesized by reverse transcription-PCR and was expressed in Escherichia coli. Recombinant protein reacted with a mouse monoclonal antibody raised against human hsp7O. Splenocytes from C57BL/6 mice immunized with recombinant hsp7O emulsified in adjuvant, but not yeast cells, reacted in vitro to the antigen. Recombinant hsp7O elicited a cutaneous delayed-type hypersensitivity response in mice immunized with protein or with viable yeast cells. Mice were injected with recombinant hsp7O and challenged intranasally with a sublethal inoculum of yeast cells. Vaccination did not confer protection in this model. Thus, recombinant hsp7O can induce a cell-mediated immune response but does not induce a protective response.