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Lupus-Prone Mice Resist Immune Regulation and Transplant Tolerance Induction.
Stocks BT, Wilhelm AJ, Wilson CS, Marshall AF, Putnam NE, Major AS, Moore DJ
(2016) Am J Transplant 16: 334-41
MeSH Terms: Animals, Autoantibodies, Autoimmunity, Cells, Cultured, Dendritic Cells, Graft Rejection, Graft Survival, Islets of Langerhans Transplantation, Lupus Erythematosus, Systemic, Lupus Nephritis, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Inbred NOD, T-Lymphocytes, Regulatory, Transplantation Tolerance
Show Abstract · Added September 16, 2015
The strongly immunogenic environment in autoimmune diseases such as lupus may pose a stringent barrier to transplantation. Despite available murine models of lupus, transplant tolerance in this setting has yet to be fully investigated in highly penetrant genetic models of disease. Such studies are of clear clinical importance because lupus is a transplant indication in which transplanted kidneys have a substantially increased risk of rejection including a role for recurrent nephritis. In the fully penetrant B6.SLE123 mouse, we determined that CD4 T follicular helper and germinal center B cells were significantly expanded compared with healthy controls. We traced this expansion to resistance of effector CD4 T and B cells in B6.SLE123 mice to regulation by either CD4 T regulatory cells (CD4Tregs) or CD8 T regulatory cells (CD8Tregs), despite demonstrating normal function by Tregs in this strain. Finally, we determined that B6.SLE123 mice resist anti-CD45RB-mediated tolerance induction to foreign islet allografts, even in the absence of islet autoimmunity. Overall, B6.SLE123 lupus-prone mice are highly resistant to transplant tolerance induction, which provides a new model of failed tolerance in autoimmunity that may elucidate barriers to clinical transplantation in lupus through further cellular and genetic dissection.
© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
0 Communities
2 Members
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17 MeSH Terms
The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.
Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE
(2008) Nat Med 14: 748-55
MeSH Terms: Animals, Boronic Acids, Bortezomib, Lupus Erythematosus, Systemic, Mice, Mice, Inbred BALB C, Mice, Inbred MRL lpr, Mice, Inbred NZB, Models, Immunological, Nephritis, Ovalbumin, Plasma Cells, Protease Inhibitors, Proteasome Inhibitors, Pyrazines, Time Factors
Show Abstract · Added September 17, 2013
Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.
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1 Members
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16 MeSH Terms
Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo.
Liu Y, Pop R, Sadegh C, Brugnara C, Haase VH, Socolovsky M
(2006) Blood 108: 123-33
MeSH Terms: Animals, Cell Survival, Disease Models, Animal, Down-Regulation, Erythroblasts, Erythropoiesis, Erythropoietin, Fas Ligand Protein, Flow Cytometry, Gene Expression Profiling, Gene Expression Regulation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Transgenic, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, fas Receptor
Show Abstract · Added August 19, 2013
Erythropoietin (Epo) is the principal regulator of the erythropoietic response to hypoxic stress, through its receptor, EpoR. The EpoR signals mediating the stress response are largely unknown, and the spectrum of progenitors that are stress responsive is not fully defined. Here, we used flow cytometry to identify stress-responsive Ter119+CD71highFSChigh early erythroblast subsets in vivo. In the mouse spleen, an erythropoietic reserve organ, early erythroblasts were present at lower frequencies and were undergoing higher rates of apoptosis than equivalent cells in bone marrow. A high proportion of splenic early erythroblasts coexpressed the death receptor Fas, and its ligand, FasL. Fas-positive early erythroblasts were significantly more likely to coexpress annexin V than equivalent, Fas-negative cells, suggesting that Fas mediates early erythroblast apoptosis in vivo. We examined several mouse models of erythropoietic stress, including erythrocytosis and beta-thalassemia. We found a dramatic increase in the frequency of splenic early erythroblasts that correlated with down-regulation of Fas and FasL from their cell surface. Further, a single injection of Epo specifically suppressed early erythroblast Fas and FasL mRNA and cell-surface expression. Therefore, Fas and FasL are negative regulators of erythropoiesis. Epo-mediated suppression of erythroblast Fas and FasL is a novel stress response pathway that facilitates erythroblast expansion in vivo.
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1 Members
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19 MeSH Terms
CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice.
Yang JQ, Chun T, Liu H, Hong S, Bui H, Van Kaer L, Wang CR, Singh RR
(2004) Eur J Immunol 34: 1723-32
MeSH Terms: Animals, Antigens, CD1, Antigens, CD1d, CD4-Positive T-Lymphocytes, Dermatitis, Disease Models, Animal, Female, Immunohistochemistry, Immunophenotyping, Interferon-gamma, Interleukin-10, Interleukin-4, Liver, Male, Mice, Mice, Inbred MRL lpr, Mice, Knockout, Nephritis, Organ Size, Thymus Gland
Show Abstract · Added December 10, 2013
Mechanisms responsible for the development of autoimmune skin disease in humans and animal models with lupus remain poorly understood. In this study, we have investigated the role of CD1d, an antigen-presenting molecule known to activate natural killer T cells, in the development of inflammatory dermatitis in lupus-susceptible MRL-lpr/lpr mice. In particular, we have established MRL-lpr/lpr mice carrying a germ-line deletion of the CD1d genes. We demonstrate that CD1d-deficient MRL-lpr/lpr mice, as compared with wild-type littermates, have more frequent and more severe skin disease, with increased local infiltration with mast cells, lymphocytes and dendritic cells, including Langerhans cells. CD1d-deficient MRL-lpr/lpr mice had increased prevalence of CD4(+) T cells in the spleen and liver and of TCR alpha beta (+)B220(+) cells in lymph nodes. Furthermore, CD1d deficiency was associated with decreased T cell production of type 2 cytokines and increased or unchanged type 1 cytokines. These findings indicate a regulatory role of CD1d in inflammatory dermatitis. Understanding the mechanisms by which CD1d deficiency results in splenic T cell expansion and cytokine alterations, with increased dermal infiltration of dendritic cells and lymphocytes in MRL-lpr/lpr mice, will have implications for the pathogenesis of inflammatory skin diseases.
0 Communities
1 Members
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20 MeSH Terms
Repeated alpha-galactosylceramide administration results in expansion of NK T cells and alleviates inflammatory dermatitis in MRL-lpr/lpr mice.
Yang JQ, Saxena V, Xu H, Van Kaer L, Wang CR, Singh RR
(2003) J Immunol 171: 4439-46
MeSH Terms: Animals, Cell Division, Dermatitis, Drug Administration Schedule, Female, Galactosylceramides, Genetic Predisposition to Disease, Injections, Intraperitoneal, Killer Cells, Natural, Lupus Nephritis, Lymphocyte Activation, Lymphocyte Count, Lymphopenia, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred MRL lpr, T-Lymphocyte Subsets
Show Abstract · Added December 10, 2013
NK T (NKT) cells expressing the invariant Valpha14-Jalpha18 TCR alpha-chain recognize glycolipid Ags such as alpha-galactosylceramide (alpha-GalCer) presented by the MHC class I-like molecule CD1d. Upon activation by alpha-GalCer, invariant NKT cells secrete multiple cytokines and confer protection in certain immune-mediated disorders. Here we have investigated the role of NKT cells in the development of inflammatory dermatitis in MRL-lpr/lpr mice, which shares features with lupus in humans. Our results show that the numbers Sand functions of NKT (TCRbeta(+)CD1d/alpha-GalCer tetramer(+)) cells, particularly of the NK1.1(-) subset, are reduced in MRL-lpr/lpr mice compared with MRL-fas/fas and/or nonautoimmune C3H/Hej and BALB/c mice. Repeated treatments with alpha-GalCer result in the expansion of NKT cells and alleviate dermatitis in MRL-lpr/lpr mice. Our results indicate that NKT cell deficiency can be corrected by repeated alpha-GalCer treatment and that NKT cells may play a protective role in inflammatory dermatitis of lupus-prone mice.
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1 Members
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18 MeSH Terms
Perforin protects against autoimmunity in lupus-prone mice.
Peng SL, Moslehi J, Robert ME, Craft J
(1998) J Immunol 160: 652-60
MeSH Terms: Animals, Autoimmune Diseases, Cell Movement, Crosses, Genetic, Disease Susceptibility, Lupus Nephritis, Lymphocytes, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Mice, Inbred MRL lpr, Mice, Knockout, Perforin, Pore Forming Cytotoxic Proteins, Survival Analysis, fas Receptor
Show Abstract · Added March 4, 2015
The roles of cytolytic regulatory mechanisms in the immune system of lupus-prone mice were examined in perforin-deficient animals bearing functional or defective (lpr) Fas Ag (CD95). Perforin-deficient Fas+ animals developed accelerated autoimmunity, characterized by increased hypergammaglobulinemia, autoantibody production, and immune deposit-related end-organ disease compared with perforin-intact counterparts. In comparison, perforin-deficient lpr animals had accelerated mortality compared with perforin-intact lpr mice, associated with the abnormal accumulation of CD3+CD4-CD8- alphabeta T cells in conjunction with unaltered hypergammaglobulinemia, autoantibody production, and immune complex renal disease. These results indicate that cytolytic lymphoid regulation plays critical roles in the immune homeostasis of lupus-prone animals, and identify perforin-mediated cytotoxicity as a specific mechanism in the regulation of systemic autoimmunity.
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1 Members
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16 MeSH Terms
The lymphoproliferation mutation in Fas locally unfolds the Fas death domain.
Eberstadt M, Huang B, Olejniczak ET, Fesik SW
(1997) Nat Struct Biol 4: 983-5
MeSH Terms: Amino Acid Sequence, Animals, Apoptosis, Humans, Lymphocyte Activation, Magnetic Resonance Spectroscopy, Mice, Mice, Inbred MRL lpr, Molecular Sequence Data, Mutation, Protein Folding, Protein Structure, Secondary, fas Receptor
Show Abstract · Added March 5, 2014
NMR studies of the lymphoproliferation mutant (V238N) of the Fas death domain indicate that helix 3 is unfolded. This local structural change abolishes binding to FADD--a protein that interacts with Fas and also contains a death domain--and causes the accumulation of autoreactive T cells.
0 Communities
1 Members
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13 MeSH Terms
Roles of interferon-gamma and interleukin-4 in murine lupus.
Peng SL, Moslehi J, Craft J
(1997) J Clin Invest 99: 1936-46
MeSH Terms: Animals, Autoantibodies, Female, Immunoglobulin Isotypes, Interferon-gamma, Interleukin-4, Kidney, Liver, Lupus Erythematosus, Systemic, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Inbred MRL lpr, Mice, Knockout, Mutation, Salivary Glands
Show Abstract · Added March 4, 2015
The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice consists of severe pan-isotype hypergammaglobulinemia, autoantibody production, lymphadenopathy, and immune complex-associated end-organ disease. Its pathogenesis has been largely attributed to helper alphabeta T cells that may require critical cytokines to propagate pathogenic autoantibody production. To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and IL-4 -/- lupus-prone mice were generated by backcrossing cytokine knockout animals against MRL/lpr breeders. IFN-gamma -/- animals produced significantly reduced titers of IgG2a and IgG2b serum immunoglobulins as well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins, but maintained comparable levels of IgG2a and IgG2b as well as autoantibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- mice, however, developed significantly reduced lymphadenopathy and end-organ disease. These results suggest that IFN-gamma and IL-4 play opposing but dispensable roles in the development of lupus-associated hypergammaglobulinemia and autoantibody production; however, they both play prominent roles in the pathogenesis of murine lupus-associated tissue injury, as well as in lpr-induced lymphadenopathy.
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1 Members
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17 MeSH Terms