Critical role for monocyte chemoattractant protein-1 and macrophage inflammatory protein-1alpha in induction of experimental autoimmune myocarditis and effective anti-monocyte chemoattractant protein-1 gene therapy.
BACKGROUND
Autoimmune myocarditis is a principal cause of heart failure among young adults and is often a precursor of dilated cardiomyopathy. Monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1alpha (MIP-1alpha) are potent chemotactic factors for mononuclear cells. The inflammatory infiltrate observed in myocardial lesions of myocarditis consists of >70% mononuclear cells. To determine their critical role in the pathogenesis of myocarditis, we inhibited mononuclear cell activation and migration to see if it would affect disease severity and disease prevalence in experimental autoimmune myocarditis (EAM).


RESULTS
In this report, we demonstrated that blockade of MCP-1 or MIP-1alpha with monoclonal antibodies significantly reduced severity of myocarditis in BALB/c mice immunized with cardiac myosin. Similar results were obtained when CCR2-/- and CCR5-/- mice were used. In CCR2-/- mice, not only disease severity but also disease prevalence was reduced. To further inhibit mononuclear cell activation and migration, we transfected the mice before inducing EAM with a dominant-negative inhibitor of MCP-1 gene (7ND). This transfection significantly reduced the disease severity, decreased mRNA expression levels, especially of the chemokines RANTES, MIP-2, IP-10, MCP-1, T-cell activation gene 3, and eotaxin in the myocardium, and resulted in a reduction in cardiac myosin-induced interleukin-1 and interleukin-4 and in an increase in interferon-gamma and interleukin-10 cytokine production by splenocytes.


CONCLUSIONS
Overall, these findings suggest that the chemokines MCP-1 and MIP-1alpha, acting through their receptors CCR2 and CCR5, are important in the induction of EAM and that inhibition of MCP-1 with 7ND gene transfection significantly reduced disease severity. This strategy may be a new feasible form of gene therapy against autoimmune myocarditis.
Göser
Stefan
S
Department of Internal Medicine III, University of Heidelberg, Germany.
Ottl
Renate
R
Brodner
Alexander
A
Dengler
Thomas J
TJ
Torzewski
Jan
J
Egashira
Kensuke
K
Rose
Noel R
NR
Katus
Hugo A
HA
Kaya
Ziya
Z
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000209:etiology / Q000628:therapy; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D019402:Macrophage Inflammatory Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D009154:Mutation; D009205:Myocarditis / Q000209:etiology* / Q000276:immunology / Q000628:therapy*; D009218:Myosins / Q000008:administration & dosage; D012333:RNA, Messenger / Q000032:analysis; D019707:Receptors, Chemokine / Q000235:genetics; D014162:Transfection; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D019402:Macrophage Inflammatory Proteins; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D009218:Myosins