Malignant mesothelioma is an aggressive tumor of serosal surfaces, such as the pleura and the peritoneum. This tumor was once rare, but its incidence is increasing worldwide, probably as a result of widespread exposure to asbestos, a factor with which it is associated. The authors review advances made in the past 5 to 10 years in the understanding, diagnosis, and management of mesothelioma.

Advances in Malignant Mesothelioma

Purpose: Myeloid suppressor (Gr-1+/CD11b+) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8+ T cells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist.

Experimental Design: The effect of the chemotherapy drug gemcitabine on the number of (Gr-1+/CD11b+) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-β.

Results: This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4+ T cells, CD8+ T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8+ T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-β markedly enhanced antitumor efficacy.

Conclusions: These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.

https://clincancerres.aacrjournals.org/content/clincanres/11/18/6713.full.pdf

Gemcitabine Selectively Eliminates Splenic Gr-1 + /CD11b + Myeloid Suppressor Cells in Tumor-Bearing Animals and Enhances Antitumor Immune Activity

Paraneoplastic neurologic syndromes are incited by a tumor outside the nervous system that produces a characteristic antigen of the nervous system. An immune response against the ectopic tumor antigen not only damages nerve tissue but also inhibits growth of the tumor.

Paraneoplastic Syndromes Involving the Nervous System

Geigy Scientific Tables

The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to alleles in HLA-DRB1. However, debate persists about the identity of the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 individuals with seropositive rheumatoid arthritis (cases) and 14,974 unaffected controls, we imputed and tested classical alleles and amino acid polymorphisms in HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1 and HLA-DRB1, as well as 3,117 SNPs across the MHC. Conditional and haplotype analyses identified that three amino acid positions (11, 71 and 74) in HLA-DRβ1 and single-amino-acid polymorphisms in HLA-B (at position 9) and HLA-DPβ1 (at position 9), which are all located in peptide-binding grooves, almost completely explain the MHC association to rheumatoid arthritis risk. This study shows how imputation of functional variation from large reference panels can help fine map association signals in the MHC.

/pdf/five-amino-acids-in-three-hla-proteins-explain-most-of-the-41prz91agk.pdf

Michael J. Garlepp

Papers

Apolipoprotein E and inclusion body myositis.

Analysis of genetic factors predisposing to the development of sporadic inclusion body myositis.

New techniques for evaluating lung immunology and immunopathology

Gene therapy of malignant mesothelioma

Immunodiagnosis of muscle disease: Use of anti achr and other autoantibodies