Influence of triple and double immunosuppressive therapy on proinflammatory gene expression during acute cellular rejection episodes.

ZAMBERNARDI, AGUSTINA; CHIODETTI ANA; DOMINIK MEIER; SCHIFFRIN EDUARDO; CABANNE, ANA; NACHMAN FABIO; CAROLINA RUMBO; GABRIEL GONDOLES; RUMBO MARTIN

Congreso; XII International Small Bowel Transplantation Symposium; 2011

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman"; mso-ansi-language:EN-US; mso-fareast-language:EN-US;} @page Section1 {size:612.0pt 792.0pt; margin:72.0pt 90.0pt 72.0pt 90.0pt; mso-header-margin:36.0pt; mso-footer-margin:36.0pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Introduction: Acute cellular rejection (ACR) is the first cause of graft loss after intestinal transplant. A better understanding of the process and an improvement of the diagnostic tools available are desirable. With this aim, we analyzed by q-PCR the relative expression of the proinflammatory genes: gamma interferon (IFNG), CXCL11, CXCL10, CCL20, and MXA in graft follow-up biopsies. Material and Methods: A total of 82 samples of 15 patients (10 pediatrics/5 adults) were analyzed. Among them, 39 showed normal histopathology and clinical condition, 20 corresponded to rejection episodes diagnosed by histopathology and the remaining 23 to different clinical conditions (abdominal collections, enteritis, non abdominal infections and others). Considering the immunosuppressive (IS) therapy at the time of sampling, two groups were identified: dual therapy (corticosteroid and tacrolimus, n=35) or triple therapy (adding sirolimus or mycophenolate mofetil, n=47). Expression of β-actin was used as normalizer and relative expression was calculated using the group of normal samples as reference. Results: Considering the clinical condition, none of the genes showed a specific increase of expression, since increments were detected either in rejection, infection, or other inflammatory conditions. However, expression of IFNG, CXCL11 and CXCL10 correlated with the severity of the ACR episodes (Table 1).  The increment of IFNG gene expression alone was associated to lymphocytes and plasma cells infiltration in the lamina propria (IFNG, p<0.001). Expression of IFNG was modulated by the immunosuppressive treatment; this was especially evident in samples with mild ACR, patients under triple IS showed lower IFNG and CXCL10 than those under double IS  (p<0.001 and p<0.025 respectively). Gene ± SE Asymptomatic ACR Mild /moderate ACR Severe ACR IFNG 3.0 ± 1.3 5.9 ± 2.7 8.3 ± 4.3 CXCL10 2.1 ± 0.7 5.6 ± 2,0 18.9 ± 13.5 CXCL11 1.3 ± 0.5 7.7 ± 4,7 11.4 ± 3.8        Table I: Relative expression calculated using the group of normal samples as reference. Conclusions: Gene expression analysis is a valuable tool to understand the biological processes ongoing during ACR. IS therapy modulates IFNG and CXCL10 gene expression. The analysis of a larger number of samples and inclusion of new genes will improve the characterization ACR process.