Cytokine-induced killer cells

Santos, MS, Gaziano, JM, Leka, LS, Beharka, AA, Hennekens, CH, and Meydani, SN, 1998. Beta-carotene-induced enhancement of natural killer cell activity in elderly men An investigation of the role of cytokines. Am J Clin Nutr 68, 164—170. 

Based upon recent controlled studies, there is considerable evidence that opioids such as morphine induce substantial effects on immune status. For example, it has been shown that morphine administration is associated with alterations in a number of immune parameters, such as natural-killer cell activity [12,13], proliferation of lymphocytes, [13, 14] antibody production [15,16], and the production of interferon [17]. Studies in our laboratory have shown that acute morphine treatment in rats suppresses splenic lymphocyte proliferative responses to both T- and B-cell mitogens, splenic natural-killer cell activity, blood lymphocyte mitogenic responsiveness to T-cell mitogens, and the in vitro production of the cytokines interleukin-2 and interferon-y [18-22], Furthermore, the immune alterations induced by morphine are dose-dependent and antagonized by the opioid-receptor antagonist, naltrexone (e.g., [22]). 

Perez, L. and Lysle, D.T., Corticotropin-releasing hormone is involved in conditioned stimulus-induced reduction of natural killer cell activity but not in conditioned alterations in cytokine production or proliferation responses, J. Neuroimmunol., 63, 1, 1995. 

IL-2 (Proleukin) is a cytokine that promotes the proliferation, differentiation, and recruitment of T and B lymphocytes, natural killer cells, and thymocytes. Human recombinant IL-2 is designated as rIL-2. rIL-2 binds to IL-2 receptors on responsive cells and induces proliferation and differentiation of T helper cells and T cytotoxic cells. It also can induce B-lymphocyte proliferation, activate macrophage activity, and augment the cytotoxicity of natural killer cells. 

BsAb 2B1 recognizes both HER2 and CD 16, the low-affinity type III Fc receptor (FcyRIII) expressed by mononuclear phagocytes and natural killer cells. In a phase I clinical study, 2B1 was shown to induce cytokine release, and several minor antitumor responses were observed (255). 

Conneely, 2001). LF has the ability to bind to the surface of several types of immune cells, which suggests that it can modulate immune functions. Both stimulatory and inhibitory effects of LF on lymphocyte proliferation have been described in the literature. LF has been reported to induce in vitro maturation of T- and B-lymphocytes, to modulate the activity of natural killer cells and to enhance the phagocytic activity of neutrophils. In mice, bovine LF has been shown to induce both mucosal and systemic immune responses (Debbabi et al., 1998). Cell-culture studies have demonstrated that LF and peptides derived from LF influence the production of various cytokines which regulate the immune and inflammatory responses of the body (Crouch et al., 1992 Shinoda et al., 1996). 

Bryostatin 1 binds to the regulatory domain of protein kinase C short-term exposure promotes activation of protein kinase C, whereas prolonged exposure promotes significant down-regulation (4). In preclinical and phase I clinical studies it had promising antitumor and immuno-modulating effects. It amplifies expansion of myeloid and erythroid progenitor cells stimulated by the cytokines GM-CSF, M-CSF, and IL-3. Similarly, it induces the production of peripheral blood mononuclear cells with enhanced lymphokine-activated killer cell activity and proliferation in the presence of IL-2 (5). 

Interferons (IFNs) are extremely potent cytokines that pos-se.ss antiviral, immunomodulating. and antiproliferative actions.- IFNs are synthesized by infected cells in response to various inducers (Fig. I l-l) and. in turn, elicit either an antiviral stale in neighboring cells or a natural killer cell response that destroys the initially infected cell (Fig. 11-2). There are three classes of human IFNs that possess signifi-ctinl aniiviral activity. Tlicsc are IFN-a (mote than 20 subtypes). IFN-/J(2 subtypes), and IFN-y. IFN- is used clini-eally in a rcconibinani fonn (called interferon alfa). IFN-fi (Betaseron) is a recombinant form marketed for the treatment of multiple sclerosis. 

Another approach to induce a GVT effect in patients who relapse following HSCT is to administer a cytokine posttransplant with immunomodulatory activity, such as interleukin-2 (IL-2)." Some beneficial effects have been observed with the use of IL-2 with respect to effects on natural killer cells and other important antitumor immune responses. Toxicities have been tolerable in most patients but can be serious and life-threatening. Studies are necessary to define the role of these cytokines in prolonging relapse-free survival after HSCT. 

Tumor hypoxia can dramatically impede the effectiveness of certain (passive) immunotherapies using cytokines (interferon-y and tumor necrosis factor-a). Hypoxia also reduces survival and proliferation of T-lymphocytes and the production of cytokines by these cells (Kim et al. 2008 Lukashev et al. 2007). Pharmacological studies have firmly established that high levels of adenosine, a pathophysiological feature of solid tumors (see Chap. 4, Sect. 4.11.12), have immunosuppressive effects (SiTKovsKY and Lukashev 2005 Ohta et al. 2006). In addition, hypoxia can alter IL-2-induced activation of lymphokine-activated killer (LAK) cells (reviewed by Chaplin et al. 2000 Kim et al. 2008 SiTKOVSKY and Lukashev 2005). The potency of treatment started to decrease at oxygen partial pressures of less than approximately 35 mmHg ( 5% O2). 

---