ABSTRACT
BACKGROUND: DRα1-mouse(m)MOG-35-55, a novel construct developed in our laboratory as a simpler and potentially less immunogenic alternative to two-domain class II constructs, was shown previously to target the MIF/CD74 pathway and to reverse clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) in DR*1501-Tg mice in a manner similar to the parent DR2ß1-containing construct. METHODS: In order to determine whether DRα1-mMOG-35-55 could treat EAE in major histocompatibility complex (MHC)-mismatched mice and to evaluate the treatment effect on central nervous system (CNS) inflammation, C57BL/6 mice were treated with DRα1-mMOG-35-55. In addition, gene expression profile was analyzed in spinal cords of EAE DR*1501-Tg mice that were treated with DRα1-mMOG-35-55. RESULTS: We here demonstrate that DRα1-mMOG-35-55 could effectively treat EAE in MHC-mismatched C57BL/6 mice by reducing CNS inflammation, potentially mediated in part through an increased frequency of M2 monocytes in the spinal cord. Microarray analysis of spinal cord tissue from DRα1-mMOG-35-55-treated vs. vehicle control mice with EAE revealed decreased expression of a large number of pro-inflammatory genes including CD74, NLRP3, and IL-1ß and increased expression of genes involved in myelin repair (MBP) and neuroregeneration (HUWE1). CONCLUSION: These findings indicate that the DRα1-mMOG-35-55 construct retains therapeutic, anti-inflammatory, and neuroprotective activities during treatment of EAE across MHC disparate barriers.
Subject(s)
Central Nervous System Diseases/drug therapy , Encephalomyelitis, Autoimmune, Experimental/drug therapy , HLA-DR alpha-Chains/therapeutic use , Inflammation/drug therapy , Macrophages/pathology , Myelin-Oligodendrocyte Glycoprotein/therapeutic use , Neuroprotective Agents/therapeutic use , Animals , CD11 Antigens/metabolism , Cell Count , Cell Survival/drug effects , Central Nervous System Diseases/pathology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/pathology , HLA-DR alpha-Chains/analysis , HLA-DR alpha-Chains/pharmacology , Inflammation/pathology , Lectins, C-Type/metabolism , Macrophages/drug effects , Macrophages/immunology , Male , Mannose Receptor , Mannose-Binding Lectins/metabolism , Mice , Mice, Inbred C57BL , Myelin-Oligodendrocyte Glycoprotein/analysis , Myelin-Oligodendrocyte Glycoprotein/pharmacology , Nerve Regeneration/drug effects , Neuroprotection/drug effects , Neuroprotective Agents/analysis , Neuroprotective Agents/pharmacology , Peptide Fragments/analysis , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Receptors, Cell Surface/metabolismABSTRACT
BACKGROUND: Low expression of HLA class II antigens has been associated with more aggressive disease in several human malignancies including adult adrenocortical tumors (ACT), but their clinical relevance in pediatric ACT needs to be investigated. PROCEDURE: This study analyzed the expression profile of three class II histocompatibility genes (HLA-DRA, HLA-DPA1, and HLA-DPB1) in 58 consecutive pediatric ACT (13 adenomas and 45 carcinomas) by quantitative real time PCR and their association with clinical and biological features. HLA-DPA1 protein level was determined by immunohistochemistry. RESULTS: A significant association (P < 0.01) was observed between lower expression levels of the three genes analyzed and poor prognostic factors such as age ≥ 4 years, tumor size ≥ 200 cm(3), tumor weight ≥ 100 g, and metastatic disease; the presence of an unfavorable event and death. Underexpression of the HLA-DRA, HLA-DPA1, and HLA-DPB1 genes were associated with lower 5-year event-free survival (EFS) (P = 0.017, P < 0.001, and P = 0.017, respectively). Cox multivariate analysis showed that HLA-DPA1 was an independent prognostic factor (P = 0.029) when analyzed in association with stage IV, age and tumor size. Significantly lower EFS was also observed in patients with negative/weak immunostaining for HLA-DPA1 (P = 0.002). Similar results were observed when only patients classified as having carcinomas were analyzed. CONCLUSION: Our results suggest that lower expression of HLA-DRA, HLA-DPA1, and HLA-DPB1 genes may contribute to more aggressive disease in pediatric ACT. HLA-DPA1 immunostaining may represent potential aggressiveness marker in this tumor.
Subject(s)
Adrenal Cortex Neoplasms/immunology , HLA-DP alpha-Chains/genetics , HLA-DP beta-Chains/genetics , HLA-DR alpha-Chains/genetics , Adolescent , Adrenal Cortex Neoplasms/mortality , Adrenal Cortex Neoplasms/pathology , Child , Child, Preschool , Female , HLA-DP alpha-Chains/analysis , HLA-DP beta-Chains/analysis , HLA-DR alpha-Chains/analysis , Humans , Infant , Male , PrognosisABSTRACT
Amalgam tattoo, the most common exogenous oral pigmentation, can sometimes be confused with melanotic lesions, being then biopsied. We present the clinicopathological characteristics of 6 biopsied cases (5 females and 1 male) of oral amalgam pigmentation. The most common location was the gingival mucosa, followed by the buccal and palatal mucosa. Morphology and distribution (stromal, perivascular, perineural, endomysial) of pigmentation was variable; there was only 1 case with fibrous capsular reaction and likewise only a single case of granulomatous foreign body reaction. Morphological variability is conditioned by the timing and amount of the pigment deposit, which is often associated with infiltration by mast cells (CD117+), as well as overexpression of metallothionein and HLA-DR at different tissue levels.
