Psychoneuroimmunology-Immunotherapy interactions

描述(申请人提供)：免疫刺激(IS)疗法在癌症患者中，当与其他干预措施相结合，并且限制机制被停用时，通常更有效。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毒剂的反应，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)过程和IS治疗之间的潜在相互作用，目的是解开潜在的机制，并加强免疫治疗。我们的研究将围绕三个相互关联的交互作用展开：(1)心理应激在癌症患者治疗前和治疗期间是常见的，但很少在免疫治疗的动物模型中模拟。应激反应通常会减少TH1并促进促炎反应，潜在地抑制IS制剂的有益影响并恶化其副作用。(2)宿主对IS制剂的生理反应包括细胞因子和应激激素的扰动，这些扰动可以抑制细胞介导的免疫(CMI)(见初步研究)，并自我限制IS方法的有效性。(3)在关键时刻，包括术后即刻，成功的IS方法可能会因为临床上公认的大手术后抑制CMI而失效。用我们最近开发的基于PNI的药理学干预措施(见初步研究)补充IS方法可以防止这种免疫抑制，从而保留IS方法的潜在好处。我们建议研究和改进三种免疫刺激剂，IL-12，聚I-C和CpG寡核苷酸(ODN)，在持续的社会压力条件下和手术后的效果。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的产生，以及对啮齿动物实验性和自发转移(MADB106、B16和3LL肿瘤)的体内抵抗。应激和IS毒剂有害影响的神经内分泌和细胞因子介体将被研究。在应激、IS治疗和手术期间，将开发和使用免疫刺激和药物阻断有害应激和细胞因子反应的综合方案。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.