Cytokine profiles in early rejection following OKT3 treatment in liver transplant patients

Abstract

OKT3 , a murine monoclonal antibody specific to the human CD3 complex, induces immunosuppression by depletion of T cells. Administration of OKT3 results in significant release of proinflammatory cytokines, such as TNFalpha and IL1beta. Liver recipients who experience rejection within 3 weeks after transplantation with OKT3 prophylaxis recover their T cells by postoperative day 10 despite complete initial clearance. We sought to analyze the role of proinflammatory and Th-1 cytokines in T cell recovery and rejection after liver transplantation with OKT3 prophylaxis. In plasma samples from 32 patients, we measured TNFalpha, IL1beta and IL6 (before transplant and on postoperative days 1, 2 and 3) and IL2, IFNgamma, sIL2R and slCAM (postoperative days 5, 7 and 10) and examined possible correlations with T-cell recovery and occurrence of rejection within 3 weeks. TNFalpha, IL1beta, and IL6 did not correlate with T-cell recovery. In patients who rejected, IL2 and IFNgamma on postoperative days 5 and 7 correlated with degree of T-cell recovery by day 10; a significant rise in sIL2R over time also correlated with T-cell recovery in this group. Our results emphasize the role of Th-1 cytokines in rejection following OKT3 induction and suggest that markers of T cell activation may predict risk.

Regulation of hepatocyte fate by interferon-γ

“…One problem that transplant recipients inevitably face is the possibility of graft rejection, which occurs in approximately 20–60% of transplant recipients [70]. Immune suppression is routinely used to induce graft acceptance and is typically aimed at suppressing the adaptive immune system, particularly the expression of Th1 cytokines such as IFN-γ [71, 72]. In a study investigating OLT in syngeneic and allogeneic rat models, allogeneic liver grafts exhibited greater hepatocyte apoptosis and less hepatocyte proliferation than syngeneic grafts after OLT [73].…”

Humanized Mouse as a Tool to Predict Immunotoxicity of Human Biologics

“…Humanized mice treated with Proleukin ® /IL-2 for 5 consecutive days at a dose of 600,000 IU demonstrated an increase in total lung weight, immune cell infiltration into organs, elevated levels of chemokines and pro-inflammatory cytokines, IFN-g, IL-12p70, IL-17A, IL-18, IL-23 and IL-33 and an immunosuppressive cytokine, IL-10 (15, 76). Additionally, percentages and absolute numbers of CD4 + T cells, CD8 + T cells, ICOS + Tregs and NK cells were upregulated, while levels of monocytes and B cells decreased (15,21,26,76). To further validate this model, we administered an anti-CD3 antibody-OKT3-to humanized mice and observed that massive amounts of chemokines and pro-inflammatory cytokines, IFN-g, TNF-a, IL-6, IL-8, MCP-1, IL-17A, IL-18, IL-23, and IL-33 were secreted predominantly at 1 h post-treatment (77,78).…”