Patologia e fisiopatologia generale - infiammazione e tumori prima parte

Effetti delle cellule Th1 e Th2 in diversi tipi di cancro e malattie

Bladder cancer: Diminuzione del numero di cellule Th1 e aumento del numero di cellule Th2 nel sangue periferico [5]

Colorectal cancer: Diminuzione del numero di cellule Th1 e aumento del numero di cellule Th2 nel sangue periferico e aumento delle citochine Th2 nel siero [6]

Cervical cancer: Linfociti derivati dal tessuto del cancro cervicale consistono principalmente di fenotipi Th2/Tc2 [8]

Gastric cancer: Riduzione del rapporto tra cellule Th1 e cellule Th2 nel sangue periferico e aumento di IL-10 nel siero [6,22]

Head and neck cancer: Elevati livelli di complessi immuni correlano con un aumento del carico tumorale e una prognosi sfavorevole [34-36]

Breast cancer: Tessuto pre-maligno: Attivazione delle cellule B e una risposta locale marcatamente sbilanciata di IgG nell'intestino [4,9]

Ulcerative colitis: Sostituzione delle cellule Th1 effettore con cellule Th2 effettore nel tessuto infiammato [11]

Asbestosis: Aumento di immunoglobuline e complessi immuni, e livelli più alti di IL-6 e IL-8 nel sangue periferico dei pazienti con asbestosi [4,10]

Barrett's esophagus: Sostituzione delle cellule Th1 effettore con cellule Th2 effettore nel tessuto infiammato [11]

HCV-related: [testo mancante]

cirrosi Diminuzione del numero di cellule Th1 e aumento del numero di cellule Th2 nel sangue periferico [4,12]Malattia ostruttiva cronica delle vie aeree I linfociti T nel lavaggio broncoalveolare dei pazienti con BPCO hanno mostrato un aumento [4,13](BPCO) dell'espressione intracellulare di citochine Th2. Ad esempio, sono state osservate risposte dei linfociti B intestinali nell'infezione è stata osservata nei pazienti trattati concolite ulcerosa, una condizione benigna con un alto rischio di Rituximab per l'artrite reumatoide o il linfoma non-Hodgkin’s.sviluppo del cancro al colon-retto [4,9]. È stato segnalato un diminuito rapporto Th1/Th2 nei linfomi epatocellulari cirrosi epatica correlata al virus dell'epatite C, una malattia epatica strettamente associata al carcinoma epatocellulare [12]. Nell'esofago di Barrett, uno stadio intermedio nella progressione dall'esofagite da reflusso aesophageal adenocarcinoma, infiltration of such as rheumatoid arthritis, Sjogren's syndrome and+ T cells) isTh1 effector cells (macrophages and CD8 SLE, with non-Hodgkin's lymphoma are undisputed;largely replaced by Th2 effector cells (IgG producing however, the association of solid tumors with autoimmu-plasma cells and mast cells) when reflux esophagitis pro- nity has not been well described [14]. Cohort studies have ]. Taken together, thesegresses to Barrett's esophagus [11 found increased risk for lung cancer in rheumatoid arthri-compelling clinical findings indicate that pronounced tis patients [14], and a modestly increased risk for allHI may underlie increased risk for neoplastic progression cancers, particularly lung cancer and hepatobiliary can-in tissues afflicted with chronic inflammatory disease cers, in SLE patients [14]. Clinical studies of patientspathologies. with systemic sclerosis have also revealed increased riskfor lung cancer, non-melanoma skincancers and breastAutoimmune disorders caused by B cell hyperactivity are cancer [19]. Mechanisms contributing to these enhancedalso associated with cancer [14]. B cells are known to cancer risks are largely elusive; however, given pro-initiate autoimmunity through several mechanistic path- nounced humoral immune responses in afflicted tissues,ways including enhanced production of autoantibodies, it is intriguing to speculate that autoantibody–antigenimmune complexes, dendritic and T cell activation and complex formation and deposition in neoplastic micro-cytokine production [15]. The pathogenic role for B cells environments might contribute. Support for this hypoth-in autoimmune disease is supported by clinical success of esis comes from a limited clinical study where advancedB cell depletion therapy using a chimeric monoclonal colon cancer patients were treated with Rituximab. Inantibody (MoAb) specific for human CD20 (e.g. Ritux- these individuals, numbers ofCD21-hyperpositiveimab in patients with rheumatoid arthritis, systemic lymphocytes were reduced in parallel with a 50% lupus erythematosus (SLE) and others [16,17]. Rituximab reduction in tumor burden with no ill-effects as a result has also found clinical efficacy in adult acute lympho- of the therapy [20]. Taken together, the clinical data blasticleukaemia (ALL) — monotherapy in patients with indicate a role for enhanced HI and inflammation, in relapsed ALL has achieved modest success, but greater combination with suppressed CMI, in the pathogenesis effects have been found in combination with chemother- of several human cancer types — mechanistic investi-apy and in treatment for minimal residual disease [18]. gation of the molecular and cellular pathways mediating Although Rituximab effectively deletes the vast majority enhanced cancer risk will surely identify new therapeutic of circulating B cells, no increased susceptibility to targets with which to combat neoplastic.disease.Current Opinion in Immunology 2007, 19:209–216 www.sciencedirect.com

Humoral immunity, inflammation and cancer Tan and Coussens 211

HI-associated cytokines as mediators of several HI and Th2-associated cytokines, such as tumor development IL-10, stimulate angiogenesis, and are therefore pro-Molecular mechanisms by which HI impacts cancer ]. Increased IL-10 expression in patients tumorigenic [22 initiation, promotion and progression are almost certainly with gastric cancer correlates with tumor angiogenesis, multifaceted (Figure 1). Cytokines derived from evolving attenuated CD8+ T cell infiltration, and poor prognosis ]. Although, the literature has implicated IL-6 in both neoplastic cells, activated resident stromal cells or infil- [22 Th1- and Th2-type responses, in several chronic inflam- trating immune cells can regulate tumor growth by affecting angiogenesis, cell survival, death or differentiation. better known to

direct Th2-type responses and play aCMI and Th1-associated cytokines, such as IFN-g, tend central role as a differentiation and growth factor ofto exhibit anti-angiogenic bioactivities [21], whereas

Figure 1Model for role of humoral immunity during inflammation-associated cancer development. Pre-malignant and malignant tissues are associated withsuppressed Th1 responses (i.e. IL-1 and IFNg) in combination with enhanced Th2 responses (i.e. IL-4, -6, -10 and -13). The latter leads toactivation of B cells that can inhibit Th1 anti-tumor immunity. Conversely, B cell activation also leads to immune complex (Ig:IC) accumulation inserum and tissue interstitia that subsequently initiates pro-inflammatory activities and recruitment of innate immune cells (e.g. macrophages,neutrophils and mast cells), possibly via C5aR and FcgRs, leading to chronic tumor-promoting inflammatory responses. C5a, generated throughclassical/alternative, thrombin and/or cellular C3-independent pathways, induces

chemotaxis of innate immune cells and modulates their function via regulation of activating versus inhibitory FcgRs. Current Opinion in Immunology 2007, 19:209–216 Tumour immunology neoplastic epithelial cells [23,24]. IL-13 promotes survival. Adoptive transfer lymphocyte (CTL) responses [29] and/or growth of selective tumor types through direct of B lymphocytes, but not serum, from wild-type mice action on neoplastic cells, in addition to suppressing to B cell-deficient mice restored tumor growth accom-CMI [25]. IL-23, a cytokine produced by dendritic cells and macrophages following bacterial exposure and Toll-like receptor engagement, is also found highly expressed in various types of human carcinomas compared with adjacent. Together, these experimental findings support the concept that B cells limit anti-tumor immunity by inhibiting Th1 and CTL responses while.

simultaneously bolsteringcent normal tissue, indicating a potential important role in Th2-effector cell pro-tumor functions.tumor development [26]. In a mouse model of chemicalcarcinogenesis, absence of IL-23 resulted in a significant reduction in local inflammatory responses in the tumor solid tumor development?microenvironment that paralleled an increase in cytotoxic Cancer patients often develop antibodies to tumor-associ-T-cell infiltration, together resulting in resistance to car- ated antigens — evidence exists to support this for c-myc,cinogenesis [26]. Thus, whereas IL-23 is not generally HER-2/neu and p53 [30]. However, production of theseconsidered as a Th2 cytokine, in this context, it is exerting antibodies does not confer protection, but, paradoxically,Th2-like cytokine bioactivities by promoting inflamma- correlates with poor prognosis and decreased survival fortory responses and inhibiting cytotoxic T cell responses.

Several human cancer types [31]. Anti-tumor antibodiesThe degree to which effectiveness of IL-23 neutralization are thought to enhance tumor growth by promoting pro-tumor immune responses and in general protecting tumor cells from CTL-mediated killing [32]. Increased levels of immunoglobulins (Ig) in neoplastic microenvironmentsThus, Th1- and Th2-associated cytokines act antagonistically in different tumor microenvironments, while in general a cytokine profile skewed toward Th2 responses [1,33]. Ig-IC formation is a significant feature of cancer development: high circulating levels of ICs are associated with increased tumor burden and poor prognosis.

The activities of Th2-associated cytokines are limited solely to their direct abilities to enhance pro-tumor pathways in patients with breast, genitourinary, and head and neck malignancies [34–36], and Ig deposition in neoplastic stroma has been reported in pre-malignant and malignant human breast and prostate tissues [1]. McDonald and colleagues [37] recently reported that deposition of extravasated Ig in tumor stroma is due to enhanced leakiness of tumor blood vessels. Using a mouse model of islet cell carcinogenesis, non-specific and epitope-specific anti-bodies (directed against extracellular matrix antigens) secreted by B-lymphocytes inhibit Th1 anti-tumor immunity and secretion of pro-inflammatory cytokines. In the context of cancer development, B-lymphocytes function as the central component of HI, in antibody production, antigen presentation, and secretion of pro-inflammatory cytokines.

nfused into tumor-bearing animals and both wereand circulating profiles of cytokines, B cells also inhibit found to preferentially localize adjacent to leaky tumorTh1-mediated anti-tumor immune responses. blood vessels.