Immunomodulatory strategies also suppressed anti-endothelial antibody production and preserved CNTF, IL-1alpha and VEGF levels. antibody production and preserved CNTF, IL-1alpha and VEGF levels. The immune deviation effects of the intrathymic HUVEC-injection were associated with an growth of CD4+CD25+Foxp3+ regulatory T cells. Pristane treatment decreased the proportion of T cells expressing receptor beta-chain, V16.1 in the lung tissue. Conclusions Our data demonstrate that interventions classically employed to induce central T cell tolerance (thymic inoculation of antigen) or to activate innate immune responses (pristane treatment) can prevent the FTI-277 HCl development of autoimmune emphysema. Background It is now increasingly acknowledged that chronic obstructive pulmonary disease FTI-277 HCl (COPD)/emphysema presents clinically as a syndrome with pulmonary and extra-pulmonary manifestations [1,2]. Chronic inflammatory mechanisms are being discussed as important factors which either trigger or maintain this chronic disorder [3-5]. Both lymphocytic infiltration of the bronchial mucosa and lung parenchyma [6,7] as well as lymph follicles in close proximity to bronchioles have been described [8]. It has been hypothesized that there may be an autoimmune component to the chronic progressive lung FTI-277 HCl tissue destruction which can persist after smoking cessation [9-12]. Recently Lee and co-workers exhibited anti-elastin autoantibodies in patients with tobacco smoking-induced emphysema [13]. Autoimmune diseases result from the propagation of self-reactive T and B lymphocytes that recognize self-antigens and mediate tissue destruction. Our group has described a rat autoimmune emphysema model which is usually characterized by anti-endothelial cell antibodies (AECA) and pathologic T lymphocytes, since both plasma as well as splenocytes have been shown to trigger emphysema after passive transfer into healthy na?ve rodents [14], suggesting that this pre-existing T cell repertoire in the lung is not sufficient to FTI-277 HCl respond to xenogeneic antigens. We reasoned that this autoimmune model of emphysema, which is based on Rabbit polyclonal to Ezrin immunization of rats with xenogeneic human umbilical vein endothelial cells (HUVEC), can be utilized to demonstrate the phenomenon of immune tolerance, because autoimmunity is due to the breakdown of central and/or peripheral tolerance. If so, then demonstration of protection against emphysematous lung destruction by immune modulation would provide distinct support for the role of an autoimmune contribution to lung destruction in this rodent model [14]. This concept has been repeatedly exhibited in the NOD (non-obese diabetic) model of autoimmune diabetes in which multiple interventions in young mice skew the immune response and prevent disease [15,16]. In the present study, we utilize interventions classically employed in experimental autoimmune models to induce central T cell tolerance by thymic inoculation of antigen [17] and to activate innate immune responses with pristane [18]. The acquisition of T cell tolerance to self occurs primarily within the thymus [19,20] and can be achieved through 3 not mutually exclusive mechanisms: clonal deletion, clonal anergy and specific suppression. Intrathymic tolerance induction by inoculation of donor bone marrow cells, spleen cells and other type of cells has been successfully used to prolong the survival of cardiac, skin and islet allografts in adult rodents [20-23]. Here we expand previous studies by utilizing an intrathymic inoculation approach in our FTI-277 HCl animal model of autoimmune emphysema. The hydrocarbon oil adjuvant pristane has been shown to induce a persistent decrease in phytohemagglutinin responsiveness, consistent with a block of polyclonal T cell proliferation [18]. By demonstrating that early immunomodulation prevents experimental emphysema in pathogen-free animals, the concept that autoimmune injury may contribute to clinical emphysema is usually further bolstered. Methods Experimental protocols The experimental protocol was approved by the Animal Care and Use Committee of the University of Colorado Denver. In our study we used 6 week aged male Sprague-Dawley rats (body weight 200 g). Animals were divided into four groups (n = 6 per group):.