Amelioration of brain pathology and behavioral dysfunction in mice with lupus following treatment with a tolerogenic peptide.
OBJECTIVE
Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is manifested by neurologic deficits and psychiatric disorders. The aim of this study was to examine SLE-associated CNS pathology in lupus-prone (NZBxNZW)F1 (NZB/NZW) mice, and to evaluate the ameliorating effects of treatment with a tolerogenic peptide, hCDR1 (human first complementarity-determining region), on these manifestations.


METHODS
Histopathologic analyses of brains from lupus-prone NZB/NZW mice treated with vehicle, hCDR1, or a control scrambled peptide were performed. The messenger RNA expression of SLE-associated cytokines and apoptosis-related molecules from the hippocampi was determined. Anxiety-like behavior was assessed by open-field tests and dark/light transfer tests, and memory deficit was assessed using a novel object recognition test.


RESULTS
Infiltration was evident in the hippocampi of the lupus-afflicted mice, and the presence of CD3+ T cells as well as IgG and complement C3 complex deposition was observed. Furthermore, elevated levels of gliosis and loss of neuronal nuclei immunoreactivity were also observed in the hippocampi of the mice with lupus. Treatment with hCDR1 ameliorated the histopathologic changes. Treatment with hCDR1 down-regulated the high expression of interleukin-1beta (IL-1beta), IL-6, IL-10, interferon-gamma, transforming growth factor beta, and the proapoptotic molecule caspase 8 in the hippocampi of the mice with lupus, and up-regulated expression of the antiapoptotic bcl-xL gene. Diseased mice exhibited increased anxiety-like behavior and memory deficit. Treatment with hCDR1 improved these parameters, as assessed by behavior tests.


CONCLUSIONS
Treatment with hCDR1 ameliorated CNS pathology and improved the tested cognitive and mood-related behavior of the mice with lupus. Thus, hCDR1 is a novel candidate for the treatment of CNS lupus.
Lapter
Smadar
S
The Weizmann Institute of Science, Rehovot, Israel.
Marom
Anat
A
Meshorer
Asher
A
Elmann
Anat
A
Sharabi
Amir
A
Vadai
Ezra
E
Neufeld
Adi
A
Sztainberg
Yejezkel
Y
Gil
Shoshana
S
Getselter
Dmitriy
D
Chen
Alon
A
Mozes
Edna
E
D000818:Animals; D000936:Antigen-Antibody Complex / Q000187:drug effects / Q000276:immunology; D001007:Anxiety / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000502:physiology; D017252:CD3 Complex / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007114:Immunization; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008569:Memory Disorders / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000936:Antigen-Antibody Complex; C494812:Bcl2l1 protein, mouse; D017252:CD3 Complex; D022801:Complementarity Determining Regions; D016207:Cytokines; D010446:Peptide Fragments; D012333:RNA, Messenger; D051020:bcl-X Protein