Gattringer M, Baranyi U, Pilat N, Hock K, Klaus C, Ramsey H E, Wrba F, Valenta R, Wekerle T
Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
Clin Exp Allergy. 2016 Feb;46(2):354-64. doi: 10.1111/cea.12661.
IgE-mediated allergy is a common disease characterized by a harmful immune response towards otherwise harmless environmental antigens. Induction of specific immunological non-responsiveness towards allergens would be a desirable goal. Blockade of costimulatory pathways is a promising strategy to modulate the immune response in an antigen-specific manner. Recently, OX40 (CD134) was identified as a costimulatory receptor important in Th2-mediated immune responses. Moreover, synergy between OX40 blockade and 'conventional' costimulation blockade (anti-CD40L, CTLA4Ig) was observed in models of alloimmunity.
We investigated the potential of interfering with OX40 alone or in combination with CD40/CD28 signals to influence the allergic immune response.
The OX40 pathway was investigated in an established murine model of IgE-mediated allergy where BALB/c mice are repeatedly immunized with the clinically relevant grass pollen allergen Phl p 5. Groups were treated with combinations of anti-OX40L, CTLA4Ig and anti-CD40L. In selected mice, Tregs were depleted with anti-CD25.
Blockade of OX40L alone at the time of first or second immunization did not modulate the allergic response on the humoral or effector cell levels but slightly on T cell responses. Administration of a combination of anti-CD40L/CTLA4Ig delayed the allergic immune response, but antibody production could not be inhibited after repeated immunization even though the allergen-specific T cell response was suppressed in the long run. Notably, additional blockade of OX40L had no detectable supplementary effect. Immunomodulation partly involved regulatory T cells as depletion of CD25(+) cells led to restored T cell proliferation.
Collectively, our data provide evidence that the allergic immune response towards Phl p 5 is independent of OX40L, although reduction on T cell responses and slightly on the asthmatic phenotype was detectable. Besides, no relevant synergistic effect of OX40L blockade in addition to CD40L/CD28 blockade could be detected. Thus, the therapeutic potential of OX40L blockade for IgE-mediated allergy appears to be ineffective in this setting.
IgE介导的过敏是一种常见疾病，其特征是对原本无害的环境抗原产生有害的免疫反应。诱导针对过敏原的特异性免疫无反应性将是一个理想的目标。阻断共刺激途径是以抗原特异性方式调节免疫反应的一种有前景的策略。最近，OX40（CD134）被确定为在Th2介导的免疫反应中起重要作用的共刺激受体。此外，在同种免疫模型中观察到OX40阻断与“传统”共刺激阻断（抗CD40L、CTLA4Ig）之间的协同作用。
我们研究了单独干扰OX40或与CD40/CD28信号联合干扰对过敏性免疫反应的影响。
在建立的IgE介导的过敏小鼠模型中研究OX40途径，其中BALB/c小鼠用临床相关的草花粉过敏原Phl p 5反复免疫。各组用抗OX40L、CTLA4Ig和抗CD40L的组合进行治疗。在选定的小鼠中，用抗CD25耗尽调节性T细胞（Tregs）。
在首次或第二次免疫时单独阻断OX40L，在体液或效应细胞水平上未调节过敏反应，但对T细胞反应有轻微调节作用。给予抗CD40L/CTLA4Ig组合可延迟过敏免疫反应，但在反复免疫后抗体产生无法被抑制，尽管从长远来看过敏原特异性T细胞反应受到抑制。值得注意的是，额外阻断OX40L没有可检测到的补充作用。免疫调节部分涉及调节性T细胞，因为耗尽CD25(+)细胞会导致T细胞增殖恢复。
总体而言，我们的数据提供了证据，表明对Phl p 5的过敏免疫反应独立于OX40L，尽管可检测到T细胞反应有所降低，对哮喘表型也有轻微影响。此外，除了CD40L/CD28阻断外，未检测到OX40L阻断的相关协同作用。因此，在这种情况下，OX40L阻断对IgE介导的过敏的治疗潜力似乎无效。
