The Autoimmune Pulmonary Fibrosis Model

The ability of in vitro generated ACAID-APCs to induce antigen-specific tolerance suppressing immune-mediated pathogenesis in non-immune-privileged tissues was shown in an autoimmune pulmonary interstitial fibrosis model called adoptively transferred-hapten immune pulmonary interstitial fibrosis (ADT-HIPIF) [43]. The ADT-HIPIF model shares the characteristics of idiopathic pulmonary interstitial fibrosis, a devastating and recurring condition in humans that occurs in about 17/100,000 individuals yearly with unknown etiology and no effective treatment. Mice that received hapten 2,4,6-trinitrobenzene sulfonic acid-sensitized cells and challenged intratracheally in the lung with the immunizing hapten developed pulmonary interstitial fibrosis. However, intravenous transfer of TGF-p2-treated 2,4,6-trinitrobenzene sulfonic acid-pulsed APCs to experimental mice even 1 day after pulmonary challenge reduced the collagen deposition and subsequent scarring in the interstitium of the lung. As in ACAID, ADT-HIPIF mice treated with tolerogenic APCs developed antigen-specific CD8 + Treg cells that suppressed the efferent response by regulating the presensitized T effector cells.

There are several interesting points worth mentioning in this study. This is the first report to show that APCs derived from mouse BM cultures acquired ACAID-tolerogenic characteristics. The BM-derived ACAID-APCs were generated from mouse BM cells using L929 cell-conditioned medium in a dish in vitro and have a phenotype of F4/80+, CD11b+, CD11cdim, CD40+, B7+ [43]. After TGF-p2 treatment, BM-APCs reduced CD40 but maintained their surface expression of F4/80 and B7 [43]. In addition, gene analyses (gene array and RT-PCR) after TGF-p2 treatment showed that chemokine receptor expression on BM-derived ACAID-APCs is modulated from CCR6high CCR7low CXCR4low to CCR6low CCR7low CXCR4high [45]. The expression pattern of chemokine receptors CCR6, CCR7, and CXCR4 on ACAID-APCs supports their unusual migration in the spleen [29]. Following AC inoculation, F4/80+ APCs that transport antigen to the spleen do not migrate to the T cell area (white pulp) of the spleen like inflammatory APCs (CCR6low CCR7high) would do in response to a chemokine (CCL19 and CCL21) gradient in the T cell area of secondary lymphoid organs. Instead they accumulate in the MZ of the spleen where they settle in close contact with T cells, MZ B cells, and NKT cells to generate Treg cells [29]. Second, Treg cells existed in both the spleen and the lung draining lymph nodes of experimental mice after ACAID-APC treatment [43]. However, it was not clear whether Treg cells were generated by ACAID-APCs in the lung draining lymph nodes or they migrated to the lymph nodes from the spleen. Third, ADT-HIPIF shares etiological and pathological characteristics with a variety of human immune-inflammatory conditions of the lung that eventuate into interstitial fibrosis; these studies provide insight into potential therapies to alter the course of pulmonary fibrosis in humans.

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