2004 General Immune System Function
2008 Kidney, Human Lupus Biology
LRI Class of 2008
Inflammation in the kidneys caused by lupus—lupus nephritis—is a common and dangerous development. For unclear reasons, lupus nephritis also tends to be particularly severe in males.
Dr. Caricchio has identified a protein—PARP-1—that protects male mice with lupus from developing inflammation and areas of dead tissue in the kidneys.
With LRI funding, he will now examine whether or not this protein plays a role in lupus-related kidney disease in human males. He will do this by studying tissue, urine, and serum from biopsies taken from both males and females with lupus, and assessing differences in the presence of the PARP-1 protein between the genders, among other factors.
Dr. Caricchio’s use of human tissue—it is classified as ‘human lupus biology’ research—holds promise for making breakthroughs directly relevant to people with lupus.
If successful, Dr. Caricchio’s findings will provide not only a better understanding of lupus kidney failure in males, but also in females and could advance the use of PARP-1 inhibitors to generate a specific therapy for this complication.
LRI Class of 2004
Dr. Caricchio had success in his previous work funded by the LRI, in 2004, for which he subsequently won NIH and other funding.
With that 2004 grant, Dr. Caricchio applied a novel approach of using a mouse model to pinpoint what role nucleosomes—genetic waste material generated during the death of cells in the body—that are programmed to die (apoptotic) may play in initiating lupus. He was building on researchers’ speculation that lupus begins when the body launches an attack on such nucleosomes.
The hope: that the model will confirm the potential of nucleosomes as targets for new lupus drugs that might reduce the severity of the immune system response in lupus.
And by studying lupus that develops without the presence of nucleosomes that are programmed to die, researchers hope to gain insight into how cell death kicks off the disease process and pinpoint exactly where the waste comes from.
The lab’s first model did, in fact, appear to show that autoantibody production is impaired in mice that cannot release nucleosomes.
Ultimately, Dr. Caricchio found direct evidence that cells programmed to die, and their by-products, are a source of lupus autoantibodies in vivo in certain lupus mouse models. And although inhibiting the generation of a single major autoantibody might not be protective against lupus, strategies to accelerate the clearance (removal) of dying cells appears to be a plausible approach to controlling lupus.
Poly(ADP-ribose) polymerase-1 regulates the progression of autoimmune nephritis in males by inducing necrotic cell death and modulating inflammation. Jog NR, Dinnall JA, Gallucci S, Madaio MP, Caricchio R. J Immunol. 2009 Jun 1;182(11):7297-306.
Lack of chromatin and nuclear fragmentation in vivo impairs the production of lupus anti-nuclear antibodies. Frisoni L, McPhie L, Kang SA, Monestier M, Madaio M, Satoh M, Caricchio R. J Immunol. 2007 Dec 1;179(11):7959-66.
Abnormal costimulatory phenotype and function of dendritic cells before and after the onset of severe murine lupus. Colonna L, Dinnall JA, Shivers DK, Frisoni L, Caricchio R, Gallucci S. Arthritis Res Ther. 2006;8(2):R49. Epub 2006 Feb 28.
Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus. Denny MF, Chandaroy P, Killen PD, Caricchio R, Lewis EE, Richardson BC, Lee KD, Gavalchin J, Kaplan MJ. J Immunol. 2006 Feb 15;176(4):2095-104.
Induction of apoptosis by the hydrocarbon oil pristane: implications for pristane-induced lupus. Calvani N, Caricchio R, Tucci M, Sobel ES, Silvestris F, Tartaglia P, Richards HB. J Immunol. 2005 Oct 1;175(7):4777-82.
Nuclear autoantigen translocation and autoantibody opsonization lead to increased dendritic cell phagocytosis and presentation of nuclear antigens: a novel pathogenic pathway for autoimmunity? Frisoni L, McPhie L, Colonna L, Sriram U, Monestier M, Gallucci S, Caricchio R. J Immunol. 2005 Aug 15;175(4):2692-701.
Dr. Caricchio won a $120K grant from the National Institutes of Health and a $250K grant from the Alliance for Lupus Research to continue the work that he started with LRI funding.
Rev. July 2010