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Muscle biopsies from patients with sporadic inclusion-body myositis (sIBM) consistently demonstrate that the inflammatory T cells almost invariably invade intact (not vacuolated) fibers, whereas the vacuolated fibers are rarely invaded by T cells. This indicates two concurrently ongoing processes, an autoimmune mediated by cytotoxic T cells and a degenerative manifested by the vacuolated muscle fibers and deposits of amyloid-related proteins. The autoimmune features of IBM are highlighted by the strong association of the disease with: a) HLA I, II antigens, in frequency identical to classic autoimmune diseases; b) other autoimmune disorders in up to 32% of the patients, autoantibodies, paraproteinemias, or immunodeficiency; c) HIV and HTLV-I infection with increasingly recognized frequency (up to 13 known cases); and d) antigen-specific, cytotoxic, and clonally expanded CD8+ autoinvasive T cells with rearranged T-cell receptor genes that persist over time, even in different muscles, and invade muscle fibers expressing MHC-I antigen and costimulatory molecules. In contrast to IBM, in various dystrophies the inflammatory cells are clonally diverse and the muscle fibers do not express MHC-I or costimulatory molecules in the pattern seen in IBM. Like other chronic autoimmune conditions with coexisting inflammatory and degenerative features (i.e., primary progressive MS), IBM is resistant to conventional immunotherapies. Recent data suggest that strong anti-T cell therapies can be promising and they are the focus of ongoing research.

Background: We previously reported that administration of elastase inhibitors reverses fatal pulmonary arterial hypertension (PAH) in rats by inducing smooth muscle cell (SMC) apoptosis. We showed in pulmonary artery (PA) organ culture that the mechanism by which elastase inhibitors induce SMC apoptosis involves repression of matrix metalloproteinase (MMP) activity and subsequent signaling through alphavbeta3-integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH., Methods and Results: In this study, we first showed in PA organ culture that MMP inhibition or alphavbeta3-integrin blockade with agents in clinical and preclinical use (SC-080 and cilengitide, respectively) mediates SMC apoptosis and regression of medial hypertrophy. We also documented similar results with an EGFR tyrosine kinase inhibitor. We then induced PAH in rats by injection of monocrotaline and, at day 21, began a 2-week treatment with SC-080, cilengitide, or the EGFR inhibitor PKI166. No vehicle- or cilengitide-treated animal survived beyond 2 weeks. Administration of SC-080 resulted in 44% survival at 2 weeks, and PKI166 therapy resulted in 78% and 54% survival in daily or 3-times-weekly treated animals, respectively. Four weeks after cessation of PKI166, we documented survivals of 50% and 23% in the 2 treatment groups, associated with reductions in pulmonary pressure, right ventricular hypertrophy, and abnormally muscularized distal arteries., Conclusions: We propose that selective blockade of EGFR signaling may be a novel strategy to reverse progressive, fatal PAH.

Purpose of Review: Scarring in the kidney results from excessive local synthesis and exogenous accumulation of extracellular matrix components. Once chronic damage is present in the biopsy, therapeutic intervention for the renal patient encounters severe limitations. It is therefore essential to determine clinical outcome preferably at a time point before the development of overt scarring. Clinical parameters and morphologic alterations in the biopsy are currently used as tools for the diagnosis of the renal disease entity and for assessment of the patient's prognosis. Expression levels of extracellular matrix and matrix-related components may serve as additive and even superior prognostic indicators to conventional parameters. We will elaborate on studies supporting this concept., Recent Findings: Several investigators have shown in experimental models for renal disease that extracellular matrix probes and related probes reflect disease progression and predict outcome. In this review, we will provide an update on the most recent studies of human renal biopsies showing that expression of extracellular matrix components, regulators of matrix degradation, and cytokines affecting matrix deposition may be employed for discrimination of diagnostic groups and predicting prognosis., Summary: Molecular techniques are expected to be used more and more for diagnostic and prognostic purposes in nephrological practice to supplement the histopathological analysis of the renal biopsy. Assessment of expression of matrix molecules, matrix-regulating cytokines, and metalloproteinases in renal kidney biopsies is helpful to distinguish patients who are at risk of developing progressive renal failure from patients who are likely to recover from renal tissue injury by natural remodeling mechanisms.