Monocytes and Macrophages

1. Monocytes and Macrophages Michael Fishbein. Role of macrophages in diagnostic interpretation of endomyocardial biopsies. Tim Johnson. Is transglutaminase the switch between inflammation and scarring in chronic allogaft nephropathy. David Kluth. Transfected macrophages in renal inflammation. Alex Magil. Monocyte/macrophages in renal inflammation. Jeremy Hughes. Resolution of injury, apoptosis and macrophages.

2. Macrophage Localisation From Gordon 2002

3. Differential Macrophage Activation Histotoxic NO generation ADCC etc IFN- TNF Reparative IGF-1 Apoptotic cells TGF Inflammatory Enzymes

4. Macrophages in Inflammation Classical activation Programmed NO generation Innate activation Non-programmed NO generation

5. How do macrophages integrate conflicting signals ? TNF INF IL-13 TGF LPS MCP-1 IL-10 IgG IL-12 RANTES C3b

6. MacrophageProgramming IFN NO generation TNF Apoptotic cell uptake Macrophages activated by certain cytokines are refractory to other activating cytokines

7. Monocytes and Macrophages Michael Fishbein. Role of macrophages in diagnostic interpretation of endomyocardial biopsies. Alex Magil. Monocyte/macrophages in renal inflammation. Jeremy Hughes. Resolution of injury, apoptosis and macrophages. David Kluth. Transfected macrophages in renal inflammation. Tim Johnson. Is transglutaminase the switch between inflammation and scarring in chronic allogaft nephropathy.

8. Michael Fishbein. Role of macrophages in diagnostic interpretation of endomyocardial biopsies. • Distinguishing between acute rejection and Quilty lesions in cardiac allograft biopsies. • Quilty lesions contain B cells and T cells but very few • macrophages. • Many macrophages in acute rejection. • Alex Magil. Monocyte/macrophages in renal inflammation. • Use of macrophage infiltration in diagnosis of humoral rejection. • Glomerular and tubulo-interstitial macrophages associated with • C4d deposition. • Presence of macrophages associated with poor outcomes

9. Jeremy Hughes. Resolution of injury, apoptosis and macrophages. • Discussed the role of macrophages in disposal of dead • and dying cells. • Macrophages the key cell in disposal of both necrotic and • apoptotic cells • Described the multiple receptors responsible for uptake of • apoptotic cells, including the phosphydyl seriene receptor. • Uptake of apoptotic cells induces an anti-inflammatory • phenotype in macrophages (and so does ligation of PSR) • Overwhelming the normal mechanisms of disposal results • in inflammation.

10. David Kluth. Transfected macrophages in renal inflammation. • Discussed the various functional types of macrophages and showed that anti-inflammatory macrophages can have profound effects in vivo. • Described the well recognised “phenotypes” - activated, innate activated, • alternatively activated, type 2 regulatory, and anti-inflammatory. • Showed that thransfected macrophages expressing either IL-4 or IL-10 but • not TGF reduce acute experimental glomerular injury. • These macrophages localise only to the kidney in which they are injected • but inflammation reduced in both kidneys. • Introduction of macrophages with blocked NFB are also anti- • inflammatory, but only in the kidney into which the cells were injected

11. Localisation of cytokine expressing macrophages Recombinant Adenoviruses Ad-IL-10 Ad-IL-4 Ad-TGF 1106 PKH26 labelled transfected macrophages injected into left renal artery

12. David Kluth. Transfected macrophages in renal inflammation. • Discussed the various functional types of macrophages and showed that anti-inflammatory macrophages can have profound effects in vivo. • Described the well recognised “phenotypes” - activated, innate activated, • alternatively activated, type 2 regulatory, and anti-inflammatory. • Showed that thransfected macrophages expressing either IL-4 or IL-10 but • not TGF reduce acute experimental glomerular injury. • These macrophages localise only to the kidney in which they are injected • but inflammation reduced in both kidneys. • Introduction of macrophages with blocked NFB are also anti- • inflammatory, but only in the kidney into which the cells were injected

13. Tim Johnson. Is transglutaminase the switch between inflammation and scarring in chronic allogaft nephropathy. • Discussed the role of tissue transglutaminases in cell death and in matrix accumulation. • Demonstrated all models of chronic renal scarring are associated • with increased expression of tissue transglutaminases. • Expression associated with increased cross linking of collagen • and with increased TGF expression. • Tubular cells were the source of tTGs in models of scarring in • native kidneys but interstitial (macrophages) in chronic scarring • in allografts.

14. Conclusions Macrophages are numerous in all forms renal injury. Macrophages have numerous different functions that may be injurious or reparative. Key issues for the future to devise a more complete understanding of the range of macrophage activities, how to identify macrophage “phenotypes” in vivo and how to manipulate macrophage function as therapy.