PMID- 16316965
OWN - NLM
STAT- MEDLINE
DCOM- 20060221
LR  - 20121115
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 112
IP  - 22
DP  - 2005 Nov 29
TI  - 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.
PG  - 3400-7
AB  - 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). METHODS AND 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.
FAU - Goser, Stefan
AU  - Goser S
AD  - Department of Internal Medicine III, University of Heidelberg, Germany.
FAU - Ottl, Renate
AU  - Ottl R
FAU - Brodner, Alexander
AU  - Brodner A
FAU - Dengler, Thomas J
AU  - Dengler TJ
FAU - Torzewski, Jan
AU  - Torzewski J
FAU - Egashira, Kensuke
AU  - Egashira K
FAU - Rose, Noel R
AU  - Rose NR
FAU - Katus, Hugo A
AU  - Katus HA
FAU - Kaya, Ziya
AU  - Kaya Z
LA  - eng
GR  - HL67290/HL/NHLBI NIH HHS/United States
GR  - HL70729/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokine CCL3)
RN  - 0 (Chemokine CCL4)
RN  - 0 (Chemokines)
RN  - 0 (Macrophage Inflammatory Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, Chemokine)
RN  - EC 3.6.4.1 (Myosins)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Autoimmune Diseases/etiology/therapy
MH  - Chemokine CCL2/*antagonists & inhibitors/genetics/*physiology
MH  - Chemokine CCL3
MH  - Chemokine CCL4
MH  - Chemokines/genetics
MH  - Chemotaxis, Leukocyte/drug effects
MH  - Disease Models, Animal
MH  - Genetic Therapy/*methods
MH  - Macrophage Inflammatory Proteins/*physiology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Knockout
MH  - Monocytes/drug effects/pathology
MH  - Mutation
MH  - Myocarditis/*etiology/immunology/*therapy
MH  - Myosins/administration & dosage
MH  - RNA, Messenger/analysis
MH  - Receptors, Chemokine/genetics
MH  - Transfection
MH  - Treatment Outcome
EDAT- 2005/12/01 09:00
MHDA- 2006/02/24 09:00
CRDT- 2005/12/01 09:00
PHST- 2005/12/01 09:00 [pubmed]
PHST- 2006/02/24 09:00 [medline]
PHST- 2005/12/01 09:00 [entrez]
AID - 112/22/3400 [pii]
AID - 10.1161/CIRCULATIONAHA.105.572396 [doi]
PST - ppublish
SO  - Circulation. 2005 Nov 29;112(22):3400-7. doi: 10.1161/CIRCULATIONAHA.105.572396.