IL-13 - Predictor of or Protector from Acute Graft Versus Host Disease?.
Authors: Hildebrandt Gerhard C. , Olkiewicz Krystyna M. , Choi Sung , Corrion Leigh A. , Liu Chen , McKenzie Andrew N. , Cooke Kenneth R. 
Published: April 2020

Experimental and clinical data suggest that acute graft vs. host disease (aGVHD) after allogeneic (allo-) stem cell transplantation (SCT) predominantly involves a Th1-type cytokine response. Paradoxically, the production of Interleukin 13 (IL-13), a typical Th2 cytokine, by donor T cells responding to host antigen in vitro was recently shown to correlate with the severity of clinical aGVHD. We used a well-established murine SCT model (BALB/c → B6) and mice deficient in IL-13 to more clearly investigate the role of IL-13 produced by donor cells in the pathogenesis of GVHD. In our first set of experiments, B6, BALB/c IL-13+/+ and BALB/c IL-13−/− T cells were stimulated with B6 splenic dendritic cells. BALB/c IL-13+/+ and IL-13−/− T cells proliferated equally to alloantigens (123718±9038 vs.100565±3083 cpm) compared to syngeneic controls (2411±349 cpm). In addition, IL-13+/+ T cells produced significant amounts of IL-13 (1882.5±301.9 pg/ml), whereas IL-13 levels in wells with IL-13−/− T cells were very low (37.7±2.1 pg/ml) and did not differ from syngeneic controls (52.9±7.4 pg/ml). Next, lethally irradiated B6 mice received bone marrow and T cells from either syngeneic B6, or allogeneic BALB/c IL-13+/+ or BALB/c IL-13−/− donors and serum cytokine levels were determined on day +7. As shown in table 1, serum levels of IL-13, IL-5, IFNγ and TNFa were all elevated in mice receiving allo-SCT from IL-13+/+ donors compared to syngeneic controls. By contrast, analysis of sera from IL-13−/− SCT recipients revealed significant reductions in IL-13 and IL-5 levels, no change in IFNγ and a significant increase in TNFa levels compared to allo controls. Subsequent experiments revealed that the altered cytokine milieu observed early after allo-SCT correlated with enhanced GVHD; day 100 survival in allo-recipients of IL13−/− SCT was significantly decreased when compared to mice transplanted with IL-13+/+ donor cells (table 1) although GVHD of the gut (table 1) and liver (data not shown) did not differ in animals surviving at day +42. In summary our data demonstrate that donor T cell production of IL-13 does not predict the severity of GVHD and may instead have a protective effect on mortality from GVHD in this system. The decrease in survival observed in recipients of IL-13−/− donor cells may be explained by 1) the significant decrease in Th2 cytokines early after SCT, 2) loss of the strong immuno-modulatory effects of IL-13 on macrophage function, and 3) the associated increase in TNFa levels observed in these animals. The previously described correlation between the in vitro production of IL-13 by donor T cells and clinical aGVHD may therefore reflect the overall activation status of these T cells rather than a direct functional link to GVHD pathophysiology.

Table 1: Serum cytokines (pg/ml) 7 days after SCT

IL-13 IL-5 IFN γ α TNF survival (day 100) gut pathology (day 42) (** p&lt; 0.01; * p &lt; 0.05; ND = not detectable) syngeneic 28.0±16.9 32.1±7.9 ND 2.2±1.5 100% 15.3±3.2 allogeneic wt 161.2±29.0 115.0±21.3 2059±320 38.5±5.1 40% 26.0±1.1 allogeneic IL-13−/− 13.7±4.8** 53.5±9.4* 2042±313 70.5±11.0* 0% 26.2±1.2