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099 inhibitory effect on arterial injury

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099 inhibitory effect on arterial injury

  1. 1. Inhibitory effect on arterial injury-induced neointimal formation by adoptive B cell transfer in Rag-1 KO mice P. Dimayuga, B. Cercek, S. Oguchi, G. N. Fredrikson, J. Yano, P. K. Shah, S. Jovinge, J. Nilsson Department of Medicine, Lund University, University Hospital MAS, Malmö, Sweden Atherosclerosis Research Center, Cedars-Sinai Medical Center, Los Angeles, California; Department of Biomedical Laboratory Science, Health and Society, Malmö University, Malmö, Sweden
  2. 2. General Findings: • Immune-deficiency results in increased neointimal formation after arterial injury in mice. • Humoral aspects of the immune system may be involved in inhibiting neointimal formation: B cells produce “natural antibodies” ?
  3. 3. Background •T cell deficiency results in increased neointima in injured rats (antibodies against T cell CD markers and nu/nu rats) Hansson, et al PNAS/Circ 1991 Remskar et al Circ Res. 2001 •CD40-CD40 ligand interaction mediates response to arterial injury Remskar et al Circ Res. 2001 •B cells implicated in bone-healing response as a limiting factor Marusic, et al LI 2000 •Homologous oxLDL immunization reduces neointimal formation in injured hypercholesterolemic rabbits Nilsson et al JACC 1997
  4. 4. Arterial Injury Activation of signaling cascades Increased expression of inflammatory proteins/ medial SMC activation Immune functions physiologic IFN-γ Immunoglobulins Immune-deficiency Vascular repair and Intimal formation
  5. 5. Hypothesis: B cells are involved in the response to arterial injury. Methods: •Injure Rag-1 KO mice and compare to WT mice. •“Rescue” Rag-1 KO mice with B cell reconstitution from spleens of WT •Repeat rescue with donor and recipients on western diet
  6. 6. Arterial Cuff Injury Tygon tube Right carotid artery
  7. 7. harvest spleen from WT mice squeeze through mesh to isolate cells add paramagnetic beads coated with T cell antibody expose solution to magnetic field and aspirate supe = negative selection of B cells classify cell population and/or spin and concentrate Inject cells into Rag-1 KO mice via tail vein Cell enrichment procedure
  8. 8. *p<0.05 vs. WT NC; † p<0.05 vs. Rag NC B cell reconstitution inhibits intimal formation in Rag-1 KO mice fed normal chow
  9. 9. B cell reconstitution inhibits intimal formation in Rag-1 KO mice fed western diet *p<0.05 vs. WT HC; † p<0.05 vs. Rag HC
  10. 10. WT HC Rag-KO Rag-1 KO Brec Effect of B cell reconstitution on intimal formation in injured Rag-1 KO mice
  11. 11. Neointimal stain for SM α-actin (western diet-fed mice) WT Rag-1 KO Rag-1 KO Brec
  12. 12. Mφ stain in arteries 21 days after injury (western diet-fed mice) WT Rag-1 KO Rag-1 KO Brec
  13. 13. IgM in injured arteries of western diet-fed mice Left contra-lateral (uninjured) Injured right carotid artery No reconstitution B cell reconstituted WT Rag-1 KO
  14. 14. WT Rag-1 KO Left contra-lateral (uninjured) Injured right carotid artery No reconstitution B cell reconstituted IgG in injured arteries of western diet-fed mice
  15. 15. Relative immunoglobulin levels in B cell reconstituted mice
  16. 16. Summary of Study •Neointimal formation after injury is inhibited in Rag-1 KO mice reconstituted with B cells regardless of diet. •Immunoglobulin presence is increased in injured arteries of WT mice and in B cell reconstituted Rag-1 KO mice.

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