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Rationale: Inhaled granulocyte/macrophage-colony stimulating factor (GM-CSF) is a promising therapy for pulmonary alveolar proteinosis (PAP) but has not been adequately studied. Objectives: To evaluate safety and efficacy of inhaled GM-CSF in patients with unremitting or progressive PAP. Methods: We conducted a national, multicenter, self-controlled, phase II trial at nine pulmonary centers throughout Japan. Patients who had lung biopsy or cytology findings diagnostic of PAP, an elevated serum GM-CSF antibody level, and a Pa O 2 of less than 75 mm Hg entered a 12-week observation period. Those who improved (i.e., alveolar-arterial oxygen difference [A-aDO 2 ] decreased by 10 mm Hg) during observation were excluded. The rest entered sequential periods of high-dose therapy (250 mg Days 1-8, none Days 9-14; 3 six cycles; 12 wk); low-dose therapy (125 mg Days 1-4, none Days 5-14; 3 six cycles; 12 wk), and follow-up (52 wk). Measurements and Main Results: Fifty patients with PAP were enrolled in the study. During observation, nine improved and two withdrew; all of these were excluded. Of 35 patients completing the high-and low-dose therapy, 24 improved, resulting in an overall response rate of 62% (24/39; intention-to-treat analysis) and reduction in A-aDO 2 of 12.3 mm Hg (95% confidence interval, 8.4-16.2; n 5 35, P , 0.001). No serious adverse events occurred, and serum GM-CSF autoantibody levels were unchanged. A treatment-emergent correlation occurred between A-aDO 2 and diffusing capacity of the lung, and high-resolution CT revealed improvement of ground-glass opacity. Twenty-nine of 35 patients remained stable without further therapy for 1 year. Conclusions: Inhaled GM-CSF therapy is safe, effective, and provides a sustained therapeutic effect in autoimmune PAP.

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A growing body of evidence indicates that genetic factors are involved in an increased risk of infection. We investigated whether mannose-binding lectin (MBL) gene polymorphisms that cause low levels of MBL are associated with the occurrence of major infections in patients, mainly bearing hematological malignancies, after high-dose chemotherapy (HDT) rescued by autologous peripheral blood stem cell transplantation (auto-PBSCT). A retrospective evaluation of 113 patients treated with HDT and auto-PBSCT revealed that the low-producing genotypes, B/B and B/LXA, were associated with major bacterial infection (P ¼ 0.0016, OR 7.9). We next performed a nation-wide large-scale study to assess the allele frequency of the MBL coding mutation in a total of 2623 healthy individuals in Japan. The frequency of allele B was estimated to be B0.2, almost the same in seven different areas of Japan. This common occurrence suggests that MBL deficiency may play an important role in the clinical settings of immunosuppression. Genes and Immunity (2005) The carbohydrate recognition domain of MBL binds to high mannose and N-acetyl-glucosamine oligosaccharides on various microorganisms, while the collagen-like domain is considered to bind to its receptors on phagocytes. 1,3 MBL activates complement independently of antibodies, which is a third pathway (lectin pathway) distinct from the classical and alternative complement activation cascade. It is therefore considered that MBL is an apical and important component of innate immunity of host defense. MBL has been shown to bind to a wide range of microorganisms including fungi, bacteria, protozoa, and viruses. 4 The serum level of MBL is dependent on various factors such as polymorphisms (in the coding region) and ethnicity and age (in the promoter region). [5][6][7] Of these factors, the structural polymorphisms at codons 52, 54, and 57 in the coding region are the most important determinants. All the three polymorphisms are caused by a single amino-acid substitution and result in the profound decrease of serum MBL in the individuals carrying the polymorphisms homozygously. Two polymorphisms in the promoter region at positions À550 and À221 also have additional, but less pronounced effects on the serum level of MBL. 5 Individuals carrying either of these three codon variants homozygously are common in different ethnic groups from 5 to 10%. 4 MBL deficiency is associated with infection in infants with immature immunity, 8,9 and patients with autoimmune disorders 10 and cystic fibrosis. 11,12 An association of MBL deficiency and infection is also reported in patients treated with conventional chemotherapy 13,14 or high-dose myeloablative chemotherapy followed by allogeneic stem cell transplantation, 15 which is not confirmed by others. 16,17 In the present study, we report an increased risk of major bacterial infection in patients carrying the MBL polymorphism when treated with high-dose chemotherapy (HDT) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). In ad...

In addition to B-cell depletion, modification of B-cell and T-cell phenotypes as well as cytokine profiles may be involved in the action of rituximab.