SummaryNickel (Ni), the main cause of contact allergy to metals, induces in vitro production of both Th1-and Th2-type cytokines in peripheral blood mononuclear cells (PBMC) from allergic subjects. Because the knowledge of the cellular immune response to other metals involved in contact allergy has been limited, we investigated the cytokine profile induced by Ni, cobalt (Co), chromium (Cr), palladium (Pd) and gold (Au) in PBMC from patients with patch test reactivity to the respective metals. PBMC from patients with patch test reactivity to Ni, Co, Cr, Au and/or Pd (n = 31) and non-allergic controls (n = 5) were stimulated in vitro with corresponding metal salts. Th1-[interleukin (IL)-2 and interferon (IFN)-g] and Th2-(IL-4 and IL-13) type cytokine responses were measured by enzyme-linked immunospot (ELISpot) and/or enzyme-linked immunosorbent assay (ELISA). All metals induced a mixed Th1-and Th2-type cytokine production in PBMC from individual patients with patch test reactivity to the corresponding metal, but not in control PBMC. Significantly higher responses in the patient versus controls were found for Cr (IL-2 and IL-13), Pd (IL-2 and IL-4), Au (IL-13 and IFN-g) (all P < 0·05) and Ni (all four cytokines; P < 0·01) but not Co. Overall, 71% (37/ 52) and 89% (81/91) of the positive and negative patch test reactivities to metals, respectively, were matched by the in vitro reactivity. In conclusion, our data suggest that sensitization to Co, Cr, Pd and Au results in a cellular immune response of a character similar to the mixed Th1-and Th2-type cytokine profile shown previously to be induced by Ni.
Plasma viremia decreases coincident with the appearance of virus-specific CD8+ T cells during acute HIV or SIV infection. This finding, along with demonstrations of viral mutational escape from CD8+ T cell responses and transient increase in plasma viremia after depletion of CD8+ T cells in SIV-infected monkeys strongly suggest a role for CD8+ T cells in controlling HIV/SIV. However, direct quantitative or qualitative correlates between CD8+ T cell activity and virus control have not been established. To directly assess the impact of large numbers of virus-specific CD8+ T cells present at time of SIV infection, we transferred in vitro expanded autologous central and effector memory-derived Gag CM9-, Nef YY9-, and Vif WY8-specific CD8+ T cell clones to acutely infected rhesus macaques. The cells persisted in PBMCs between 4 and 9 d, but were not detected in gut-associated lymphoid tissue or lymph nodes. Interestingly, a high frequency of the infused cells localized to the lungs, where they persisted at high frequency for >6 wk. Although persisting cells in the lungs were Ag reactive, there was no measurable effect on virus load. Sequencing of virus from the animal receiving Nef YY9-specific CD8+ T cells demonstrated an escape mutation in this epitope <3 wk postinfection, consistent with immune selection pressure by the infused cells. These studies establish methods for adoptive transfer of autologous SIV-specific CD8+ T cells for evaluating immune control during acute infection and demonstrate that infused cells retain function and persist for at least 2 mo in specific tissues.
Nickel (Ni 2þ ) elicits production of functionally distinct cytokines in vitro, but the relation between the cytokine profile and the degree of the allergic reaction in vivo needs to be better defined in order to improve the understanding of the immunological mechanisms involved in contact allergy and to facilitate development of in vitro diagnostics. The aim of the study was to define Th1-type [interferon-g (IFN-g)], Th2-type [interleukin-4 (IL-4), IL-5 and IL-13] and regulatory (IL-10) cytokine responses to Ni 2þ in peripheral blood mononuclear cells (PBMC) from subjects with varying patch test reactivity to Ni 2þ . The study included subjects with strong (þ3), moderate (þ2), weak (þ1) or negative (controls) patch test reactivity to Ni 2þ (n ¼ 10 per group). All þ3 and þ2 subjects but only three þ1 subjects had a clinical history of contact allergy to Ni 2þ . Cytokine production of PBMC stimulated with Ni 2þ was determined by enzyme-linked immunospot and/or enzyme-linked immunosorbent assay. Ni 2þ elicited significant production of all cytokines in PBMC from patch-test-positive subjects versus controls with a positive correlation between each cytokine and the patch test reactivity as well as with other cytokines. More subjects responded to Ni 2þ above cut-off values with Th2-type cytokines as compared with IFN-g or IL-10; 100% of þ3, 80% of þ2, 50% of þ1 and 0% of control subjects displayed reactivity to Ni 2þ based on IL-4 and IL-13 assays. Despite the prevailing view of Ni 2þ allergy as a type-1-mediated condition, the in vivo reactivity to Ni 2þ correlated with a mixed Th1-type, Th2-type and regulatory cytokine response to Ni 2þ in vitro. The results accentuate the importance of type 2 responses in contact allergy and also demonstrate that IL-4 and IL-13 are reliable markers for Ni 2þ allergy.
Naïve Indian rhesus macaques were immunized with a mixture of optimized plasmid DNAs expressing several SIV antigens using in vivo electroporation via the intramuscular route. The animals were monitored for the development of SIV-specific systemic (blood) and mucosal (bronchoalveolar lavage) cellular and humoral immune responses. The immune responses were of great magnitude, broad (Gag, Pol, Nef, Tat, Vif), long-lasting (up to 90 weeks post 3rd vaccination) and were boosted with each subsequent immunization, even after an extended 90 week rest period. The SIV-specific cellular immune responses were consistently more abundant in BAL than in blood, and were characterized as predominantly effector memory CD4 + and CD8 + T cells in BAL and as both central and effector memory T cells in blood. SIV-specific T cells containing Granzyme B were readily detected in both blood and BAL, suggesting the presence of effector cells with cytolytic potential. DNA vaccination also elicited long-lasting systemic and mucosal humoral immune responses, including the induction of Gag-specific IgA. The combination of optimized DNA vectors and improved intramuscular delivery by in vivo electroporation has the potential to elicit both cellular and humoral responses and dissemination to the periphery, and thus to improve DNA immunization efficacy.
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