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The study, Novak and Rizk say, largely validates the four-hit hypothesis of IgA nephropathy pathogenesis: 1) Patients with IgA nephropathy have elevated levels of circulatory galactose-deficient IgA1; 2) This leads to development of autoantibodies, mostly of the IgG subclass; 3) The IgG autoantibodies bind galactose-deficient IgA1 to form pathogenic immune complexes; and 4) Those pathogenic immune complexes deposit in glomeruli to incite kidney injury. Further support for this hypothesis comes from multiple findings. For example, previous studies showed that IgA1 immunodeposits in IgA nephropathy are enriched for galactose-deficient IgA1, likely originating from the IgA1-IgG complexes formed in the circulation. This study thus provided a key piece of evidence for the pathogenic role of IgG autoantibodies in IgA nephropathy. At UAB, Novak is professor in the UAB Department of Microbiology and Rizk is associate professor in the
UAB Department of Medicine’s Division of Nephrology. She also directs clinical trials research in that division. Co-authors with Rizk and Novak in the JASN paper, “Glomerular immunodeposits of patients with IgA nephropathy are enriched for IgG autoantibodies specific for galactose-deficient IgA1,” are Manish K. Saha and Bruce A. Julian, Division of Nephrology, UAB Department of Medicine; Stacy Hall, Rhubell Brown and Zhi-Qiang Huang, UAB Department of Microbiology; and Huma Fatima and Lea Novak, UAB Department of Pathology. Jan Novak and Bruce Julian designed the study. Support came from National Institutes of Health grants DK078244 and DK082753, and from a gift from the IGA Nephropathy Foundation of America. Manish Saha had support from NIH T32 training grant DK07545.
Shevde’s Research Featured by Department of Defense The research of Lalita Shevde-Samant,
Ph.D., Professor, Molecular & Cellular Pathology, was featured by the Department of Defense’s Congressionally Directed Medical Research Programs in an article on their website, titled, “Reprogramming the Pro-Tumorigenic Immune Microenvironment to AntiTumorigenic in Breast Cancer.” The piece features breast cancer research, for which Shevde received follow-on funding through the Department of Defense’s (DoD’s) BCRP with a Breakthrough Funding Level 2 Award.
LALITA SHEVDESAMANT, PHD
Shevde-Samant is Associate Director for Education and Training for the O’Neal Comprehensive Cancer Center at UAB. In February, the Breast Cancer Research Foundation of Alabama presented $1 million — its largest donation to date — to the O’Neal Comprehensive Cancer Center. This annual donation provides pilot money for clinical research projects, including Samant’s investigation of the hyperglycemic state of triple negative breast cancers. Triple negative cancer cells have been shown to be more aggressive and capable of suppressing the immune system, preventing it from recognizing and killing the cancer cells. With BCRFA funding, Samant and her team will now examine whether combining a diabetes drug with a treatment
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that targets triple negative breast cancer cells will improve outcomes. This study will likely lead to a clinical trial for diabetic triple negative breast cancer patients. In the article, Dr. Shevde stated, “We established a new concept that breast cancer cells mediate a ‘conversation’ or a crosstalk with tumor-infiltrating macrophages via Hedgehog ligands that act as ‘conversational’ molecules; this results in immense molecular changes in macrophages that functionally recalibrates them to an immune-suppressive, tumor-promoting state. I am very grateful to the DoD BCRP for funding my research program over the past several years on Hedgehog signaling; cumulatively, these investments have enabled me to take on new challenges to modify the breast tumor microenvironment towards eliminating breast cancer.” Her work has led to the discovery of this novel signaling paradigm. From the article,“Many of the macrophage-targeting treatments currently in clinical trials abrogate not just the recruitment of M2 macrophages but M1 as well. Thus, more targeted approaches, such as the one Dr. Shevde is taking, are needed so as to specifically target the tumor-promoting macrophages while preserving the function and integrity of the tumor-killing M1 macrophages.”
