Targeting of macrophage activity by adenovirus-mediated intragraft overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 ameliorates adenovirus-mediated chronic graft injury, whereas stimulation of macrophages by overexpression of IFN-gamma accelerates chronic graft injury in a rat renal allograft model.
Adenovirus (Ad)-mediated gene transfer of immunoregulatory molecules prevents acute allograft rejection. It is here analyzed for the first time whether this approach may prevent the development of chronic renal allograft injury in rats. Renal allografts (F344-->Lewis rat) were ex vivo transduced in group I with control Ad-construct, group II with three different therapeutic Ad-constructs expressing the immunoregulatory molecules vIL-10, TNFRp55-Ig, and IL-12p40, and group III with AdIFN-gamma. Group IV served as untreated controls. Control grafts (IV) showed increasing proteinuria during the 24-wk follow-up. Chronic graft injury was accelerated by Ad-control (I) and even more by AdIFN-gamma (III). All rats carrying the AdIFN-gamma-transduced grafts died within 12 to 13 wk by advanced chronic renal failure associated with strong immune cell infiltration and immune gene expression. By contrast, the Ad-therapy group II showed less inflammation and improved graft histology and function if compared with the groups I and III. Moreover, significantly less infiltrating ED-1(+) macrophages and an improved histologic score even if compared with untreated controls (IV) was observed. However, after disappearance of therapeutic gene expression, group II showed increasing proteinuria probably as result of late T cell activation to the Ad-encoded proteins. Ex vivo transduction of allografts with Ad-control or even more AdIFN-gamma expression promotes intragraft inflammation and chronic graft injury. Targeting macrophage activation by a cocktail of therapeutic genes improved the results. These data support the pathogenetic role of cytokines in chronic graft injury; however, they also show the limitations of the Ad-mediated gene transfer.
Yang
Jun
J
Institute of Medical Immunology, Charité-Campus Mitte, Humboldt University, Berlin, Germany.
Reutzel-Selke
Anja
A
Steier
Christoph
C
Jurisch
Anke
A
Tullius
Stefan Günter
SG
Sawitzki
Birgit
B
Kolls
Jay
J
Volk
Hans-Dieter
HD
Ritter
Thomas
T
D000256:Adenoviridae / Q000235:genetics; D000257:Adenoviridae Infections / Q000473:pathology; D000818:Animals; D015870:Gene Expression; D005822:Genetic Vectors; D007143:Immunoglobulin Heavy Chains / Q000627:therapeutic use*; D007142:Immunoglobulin gamma-Chains; D007158:Immunologic Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000009:adverse effects / Q000627:therapeutic use; D016753:Interleukin-10 / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000627:therapeutic use*; D053762:Interleukin-12 Subunit p40; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016030:Kidney Transplantation; D008264:Macrophages / Q000187:drug effects* / Q000502:physiology; D008297:Male; D021122:Protein Subunits / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D014184:Transplantation, Homologous; D014764:Viral Proteins / Q000627:therapeutic use*
C066460:BCRF1 protein, Human herpesvirus 4; D007143:Immunoglobulin Heavy Chains; D007142:Immunoglobulin gamma-Chains; D007166:Immunosuppressive Agents; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D016753:Interleukin-10; D018664:Interleukin-12; C099374:Ro 45-2081; D007371:Interferon-gamma