Th2 T cell immune-driven inflammation plays an important role in allergic asthma. We studied the effect of counterbalancing Th1 T cells in an asthma model in Brown Norway rats that favors Th2 responses. Rats received i.v. transfers of syngeneic allergen-specific Th1 or Th2 cells, 24 h before aerosol exposure to allergen, and were studied 18–24 h later. Adoptive transfer of OVA-specific Th2 cells, but not Th1 cells, and OVA, but not BSA exposure, induced bronchial hyperresponsiveness (BHR) to acetylcholine and eosinophilia in a cell number-dependent manner. Importantly, cotransfer of OVA-specific Th1 cells dose-dependently reversed BHR and bronchoalveolar lavage (BAL) eosinophilia, but not mucosal eosinophilia. OVA-specific Th1 cells transferred alone induced mucosal eosinophilia, but neither BHR nor BAL eosinophilia. Th1 suppression of BHR and BAL eosinophilia was allergen specific, since cotransfer of BSA-specific Th1 cells with the OVA-specific Th2 cells was not inhibitory when OVA aerosol alone was used, but was suppressive with OVA and BSA challenge. Furthermore, recipients of Th1 cells alone had increased gene expression for IFN-γ in the lungs, while those receiving Th2 cells alone showed increased IL-4 mRNA. Importantly, induction of these Th2 cytokines was inhibited in recipients of combined Th1 and Th2 cells. Anti-IFN-γ treatment attenuated the down-regulatory effect of Th1 cells. Allergen-specific Th1 cells down-regulate efferent Th2 cytokine-dependent BHR and BAL eosinophilia in an asthma model via mechanisms that depend on IFN-γ. Therapy designed to control the efferent phase of established asthma by augmenting down-regulatory Th1 counterbalancing mechanisms should be effective.

SUMMARYChemical allergens of different types, those that cause in humans allergic contact dermatitis or occupational asthma, induce in mice divergent immune responses characteristic, respectively, of T-helper 1 (Th1)-and Th2-type cell activation. Such responses are associated with the development of different cytokine secretion patterns by draining lymph node cells (LNC), such that contact allergens stimulate vigorous interferon-g (IFN-g) production, but little secretion of the Th2 cytokines interleukin-4 and interleukin-10 (IL-4 and IL-10), whereas the converse pattern is provoked by respiratory allergens. Using selective depletion with antibody and complement we have here examined the relative contribution of CD4 þ and CD8 þ T lymphocytes to the cytokine secretion patterns of draining LNC isolated from mice sensitized to chemical allergens. Mice received repeated topical applications of respiratory allergens, trimellitic anhydride (TMA) or diphenylmethane diisocyanate (MDI), or of contact allergens 2,4-dinitrochlorobenzene (DNCB) or formaldehyde. Thirteen days following the initiation of exposure the production by draining LNC of IL-10, IFN-g and mitogen (concanavalin A)-inducible IL-4 was measured by enzyme-linked immunosorbent assay (ELISA) after various periods of culture. It was found that the high levels of IL-4 and IL-10 secretion stimulated by TMA or MDI, and the lower levels of these cytokines induced by DNCB or formaldehyde, were in all cases dependent upon the presence of CD4 þ cells. In contrast, the comparatively high concentrations of IFN-g observed following exposure to contact allergens were found to be derived from CD4 þ cells, and in the case of DNCB from CD8 þ cells also. The low levels of IFN-g induced by treatment with TMA or MDI were associated largely or wholly with CD8 þ cells. These data indicate that the type 2 cytokine responses induced to different extents by both contact and respiratory chemical allergens are almost exclusively a function of CD4 þ cells, but that IFN-g is produced by either CD4 þ and CD8 þ cells in the case of contact allergens or largely by CD8 þ cells in the case of chemical respiratory allergens.

It has been demonstrated previously that repeated exposure of mice to chemical allergens of different types results in the development of qualitatively divergent immune responses characterized by the production by draining lymph node cells (LNC) of distinct cytokine patterns. Chronic exposure of mice to contact allergens, such as 2,4-dinitrochlorobenzene (DNCB), resulted in the secretion by LNC of low or undetectable levels of interleukins 4 and 10 (IL-4 and IL-10), but comparatively high levels of interferon γ (IFN-γ); the latter cytokine being produced by both CD4+ and CD8+ cells. In contrast, chronic exposure of mice to trimellitic anhydride (TMA), a respiratory allergen associated in humans with occupational asthma, induced instead the production by LNC of relatively high concentrations of IL-4 and IL-10, but little IFN-γ. The low levels of IFN-γ secretion which were provoked by treatment with TMA were shown to derive from CD8+ cells exclusively. In the present investigations we have sought to determine whether the polarized responses observed following repeated exposure to these chemical allergens are reflected by cytokine secretion patterns provoked by primary exposure. To this end, mice of BALB/c strain were exposed epicutaneously daily for 3 consecutive days to concentrations of DNCB and TMA (1 and 10%, respectively), or to oxazolone, another contact allergen (0.25%), that resulted in substantial proliferative activity in draining lymph nodes. The production by draining LNC of IFN-γ and of mitogen-inducible IL-4 was measured by enzyme-linked immunosorbent assay and the relative contribution of CD4+ and CD8+ cells to the patterns of cytokine secretion observed was analyzed using both positive and negative selection methods. It was found that primary exposure to DNCB, oxazolone and TMA each resulted in the production by LNC of both IFN-γ and IL-4. Selective depletion of, or enrichment for, CD4+ and CD8+ cells revealed that only CD4+ cells elaborated mitogen-inducible IL-4. Depletion of neither CD4+ nor CD8+ cells compromised the production by TMA- or DNCB-activated LNC of IFN-γ, although positively selected CD8+ cells were considerably less able than CD4+ cells to elaborate this cytokine, presumably secondary to a lack of appropriate accessory cells. Taken together the results demonstrate that early during immune responses to DNCB or oxazolone and TMA there is no evidence for the selectivity of cytokine secretion patterns that characterizes responses following more chronic exposure. Moreover, it is clear that exposure to TMA initially induces the production of IFN-γ by both CD4+ and CD8+ cells, whereas after more chronic treatment the secretion of this cytokine is a function of CD8+ cells exclusively. Collectively, these results indicate that the polarized responses that develop in mice following chronic exposure to different classes of chemical allergen are not reflected by the characteristics of primary immune responses. As such the development of qualitatively divergent immune responses to chemical aller...

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