**5.1 NKT cells and cytokines**

NKT cells are resident in the large bowel and increase in number in the colorectal cancer tissue [26]. The NKT cells have a limited T cell repertoire, and the restricted types are called invariant types of NKT (iNKT) cells. During the onset of intestinal rejection, the α chain 24 (TCRVα24) and β chain 11 (TCRVβ11) on iNKT cells are positively stained (**Figure 4A** and **B**) [17]. iNKT cells are mainly involved in innate immunity against glycolipids with the assistance of CD1d + dendritic cells [27]. Since iNKT cells are not identified in the small intestine of healthy donors before transplantation, this finding to be an indicator of ACR [17, 28].

Th1 cytokines, such as interferon-gamma (IFN-γ), generally act on the differentiation of CTLs, which promote rejection, while Th2 cytokines may suppress ACR of SBT. TCRVα24 (+) invariant NKT (iNKT) cells are positive for interleukin 4 (IL-4) in allografts of the intestine during rejection (**Figure 4C** and **D**) [8]. The apoptosis of iNKT cells are observed at the onset of rejection (**Figure 4E** and **F**), indicating that a part of apoptotic cells in the lamina propria are iNKT cells (**Figure 2**, lower right). CD1d+ dendritic cells are detected during the rejection process at the same time that the rejection progressed (**Figure 4G** and **H**). The involvement of iNKT cells in the rejection reaction has been discussed previously, and there is also an experimental report regarding their involvement in tolerance [29, 30]. However, the involvement of iNKT cells in rejection has not yet become apparent [31]. Furthermore, the mechanism by which the expression of IL-4 is directly involved in mucosal immune regulation remains unclear. However, IL-4 may suppress the action of CTLs that cause rejection. On the other hand, iNKT cells expressed FasL, indicating that they are activated in ACR (**Figure 4I**).

In addition, increased IL-5 production is also observed at the onset of rejection. IL-5 promotes eosinophil differentiation and chemotaxis [32]. This increase in production may explain the large number of eosinophils infiltrating the mucosa at the time of rejection [17]. Conventional T cells and iNKT cells may secrete IL-5 [17]. The role of eosinophils in rejection has often been debated [33] and there is a discussion on whether eosinophils may be the target of rejection therapy [34]. An increase in the rejection of eosinophils has also been reported in the transplanted liver [35]. In the small intestine, the presence of the mucosal immune system may further complicate the graft's immunological environment. Increased eosinophils, however, are histologically detectable and may provide useful information for the diagnosis of rejection, even in small bowel transplant grafts [5]. As a result of an imbalance in mucosal immunity, excess production of IL-4 and IL-5 may damage the mucosal epithelium. The administration of immunosuppressive drugs acts on iNKT cells in addition to cytotoxic T cells. Therefore, the distribution of immunocompetent lymphocytes in the mucosa is disturbed, and the treatment protocol should be developed further.
