Psychoneuroimmunology-Immunotherapy interactions

描述（由申请人提供）：免疫刺激（IS）治疗在癌症患者中通常在与其他干预措施联合使用时更有效，并且当限制机制被停用时。已知各种应激源、神经内分泌反应和细胞因子可以调节免疫能力，因此可以调节对IS药物的反应，并可能抑制其治疗效果。在这里，我们旨在研究心理-神经-免疫（PNI）过程与IS治疗之间潜在的相互作用，旨在揭示潜在的机制，并加强免疫治疗。我们的研究将围绕三个相互关联的相互作用展开：(1)IS治疗前和治疗期间的心理压力在癌症患者中很常见，但很少在免疫治疗的动物模型中模拟。应激反应通常会降低TH1并促进促炎反应，潜在地抑制IS药物的有益作用并加剧其副作用。(2)宿主对IS药物的生理反应包括细胞因子和应激激素的扰动，这些干扰可以抑制细胞介导免疫（CMI）（见初步研究），并自我限制IS方法的疗效。(3)在关键时刻，包括术后初期，成功的IS入路可能会因临床证实的大手术后CMI的抑制而失效。用我们最近开发的基于pni的药物干预来补充IS方法（见初步研究）可以防止这种免疫抑制，从而保留IS方法的潜在益处。我们建议研究和提高三种免疫刺激剂，IL-12，聚I-C和CpG寡聚脱氧核苷酸（ODN）在持续的社会压力条件下和手术后的疗效。结果将包括NK激活标记物和细胞毒性，细胞因子水平及其诱导产生，以及啮齿类动物（MADB106， B16和3LL肿瘤）对实验和自发转移的体内抗性。神经内分泌和细胞因子介质的有害影响的应激和IS药物将进行研究。将开发免疫刺激和有害应激和细胞因子反应的药物阻断的综合方案，并在应激、IS治疗和手术中使用。所获得的知识可以减少副作用，提高手术前后免疫治疗的疗效，潜在地提高癌症患者的存活率。

DESCRIPTION (provided by applicant): Immuno-stimulatory (IS) therapy in cancer patients is often more effective when combined with other interventions, and when limiting mechanisms are deactivated. Various stressors, neuroendocrine responses, and cytokines are known to modulate immune competence, and can thus modulate responses to IS agents and potentially dampen their therapeutic efficacy. Here we aim at studying potential interactions between psycho-neuro-immunological (PNI) processes and IS treatments, with the intention of unraveling underlying mechanisms, and potentiating immunotherapy. Our studies will revolve around three interrelated interactions: (1) Psychological stress before and during IS therapy is common in cancer patients, but is rarely simulated in animal models of immunotherapy. Stress responses often reduce TH1 and promote proinflammatory responses, potentially dampening beneficial impact of IS agents and worsening their side effects. (2) The host physiological response to IS agents includes perturbations in cytokines and stress hormones that can suppress cell mediated immunity (CMI) (see Preliminary Studies) and self-limit the efficacy of IS approaches. (3) At critical times, including the immediate post-operative period, successful IS approaches could be rendered ineffective by the clinically well-established suppression of CMI following major surgeries. Supplementing IS approaches with our recently developed PNI-based pharmacological interventions (see Preliminary Studies) can prevent such immune suppression, thus preserving the potential benefits of IS approaches. We propose to study and improve the efficacy of three immunostimulatory agents, IL-12, poly I-C, and CpG oligodeoxynucleotides (ODN), under ongoing social stress conditions and following surgery. Outcomes will include NK activation markers and cytotoxicity, cytokine levels and their induced production, and in vivo resistance to experimental and spontaneous metastasis in rodents (MADB106, B16, and 3LL tumors). Neuroendocrine and cytokine mediators of the deleterious effects of stress and of IS agents will be studied. Integrated protocols of immune stimulation and pharmacological blockade of deleterious stress and cytokine responses will be developed and used during stress, IS treatment, and surgery. The knowledge gained could reduce side effects and enhance the efficacy of immunotherapy before and after surgery, potentially increasing survival rates in cancer patients.