Hoft D F, Eickhoff C S
Department of Internal Medicine, Saint Louis University Health Sciences Center, Missouri 63110, USA.
Infect Immun. 2002 Dec;70(12):6715-25. doi: 10.1128/IAI.70.12.6715-6725.2002.
Chagas' disease results from infection with Trypanosoma cruzi, a protozoan parasite that establishes systemic intracellular infection after mucosal invasion. We hypothesized that ideal vaccines for mucosally invasive, intracellular pathogens like T. cruzi should induce mucosal type 2 immunity for optimal induction of protective secretory immunoglobulin A (IgA) and systemic type 1 immunity protective against intracellular replication. However, differential mucosal and systemic immune memory could be difficult to induce because of reciprocal inhibitory actions between type 1 and type 2 responses. To test our hypotheses, we investigated the protective effects of type 1 and type 2 biased vaccines against mucosal and systemic T. cruzi challenges. Intranasal vaccinations were given with recombinant interleukin-12 (IL-12)- and IL-4-neutralizing antibody (Ab) for type 1 immune bias, or recombinant IL-4 and gamma interferon-neutralizing Ab for type 2 immune bias. Cytokine RNA and protein studies confirmed that highly polarized memory immune responses were induced by our vaccination protocols. Survival after virulent subcutaneous T. cruzi challenge was used to assess systemic protection. Mucosal protection was assessed by measuring the relative inhibition of parasite replication in mucosal tissues early after oral T. cruzi challenge, using both PCR and quantitative culture techniques. As expected, only type 1 responses protected against systemic challenges (P < 0.01). However, contrary to our original hypothesis, type 1 responses optimally protected against mucosal challenges as well (P < 0.05). Type 1 and type 2 biased vaccines induced similar secretory IgA responses. We conclude that future vaccines for T. cruzi and possibly other mucosally invasive, intracellular pathogens should induce both mucosal and systemic type 1 immunity.
恰加斯病由克氏锥虫感染引起，克氏锥虫是一种原生动物寄生虫，在侵入黏膜后会引发全身性细胞内感染。我们推测，对于像克氏锥虫这样具有黏膜侵袭性的细胞内病原体，理想的疫苗应诱导黏膜2型免疫，以最佳方式诱导产生保护性分泌型免疫球蛋白A（IgA），并诱导全身性1型免疫以抵御细胞内复制。然而，由于1型和2型反应之间的相互抑制作用，可能难以诱导出不同的黏膜和全身性免疫记忆。为了验证我们的假设，我们研究了偏向1型和2型的疫苗对黏膜和全身性克氏锥虫攻击的保护作用。通过鼻内接种重组白细胞介素12（IL - 12）中和抗体和IL - 4中和抗体以偏向1型免疫，或接种重组IL - 4和γ干扰素中和抗体以偏向2型免疫。细胞因子RNA和蛋白质研究证实，我们的疫苗接种方案诱导了高度极化的记忆免疫反应。通过强毒力皮下接种克氏锥虫后的存活率来评估全身性保护作用。在口服克氏锥虫攻击后早期，使用PCR和定量培养技术，通过测量黏膜组织中寄生虫复制的相对抑制来评估黏膜保护作用。正如预期的那样，只有1型反应能抵御全身性攻击（P < 0.01）。然而，与我们最初的假设相反，1型反应对黏膜攻击也具有最佳保护作用（P < 0.05）。偏向1型和2型的疫苗诱导出相似的分泌型IgA反应。我们得出结论，未来针对克氏锥虫以及可能其他具有黏膜侵袭性的细胞内病原体的疫苗应同时诱导黏膜和全身性1型免疫。
