Search

Memory T cells are a significant barrier to the induction of transplant tolerance. Our previous study demonstrated that multiple applications of anti-CD44 monoclonal antibody (mAb) could significantly inhibit CD4(+) memory T cells from mediating rejection of cardiac allografts. Now, we sought to explore the effect and mechanism of anti-CD44 mAb on the rejection of islet allografts and xenografts mediated by CD4(+) memory T cells.In this study, we first engrafted skin grafts of C57BL/6 (B6) mice or Dark Agouti (DA) rats onto BALB/c mice to induce donor-reactive memory T cells. We adoptively transferred purified CD4(+) memory T cells to BALB/c origin nude mice and then transplanted islet allografts and xenografts to produce the Allo-Tx and Xeno-Tx models, respectively. We subsequently administered multiple anti-CD44 mAb and observed changes in the survival times of the islet grafts.In the Allo-Tx model, the mean survival time (MST) of the grafts was 7.7 days in the isotype group, and 20.3 days in the anti-CD44 group. In the Xeno-Tx model, the MST of the grafts was 7.2 days in the isotype group and 8.2 days in the anti-CD44 group. Compared with the isotype group, CD4(+) T cells on the grafts in the anti-CD44 group were significantly decreased in both the Allo-Tx and Xeno-Tx models, but the proportion of CD4(+) memory T cells in the spleens and draining lymph nodes of the recipient nude mice in the anti-CD44 group was significantly decreased in the Allo-Tx model, while it was increased in the Xeno-Tx model. The production of donor-specific IgG antibody in the anti-CD44 group did not vary in the Allo-Tx model, while it was markedly elevated in the Xeno-Tx model. Furthermore, the expression of interferon gamma in the anti-CD44 group was markedly decreased in both the Allo-Tx and Xeno-Tx models, while the expression of IL-4 in the anti-CD44 group was significantly increased only in the Xeno-Tx model.Multiple applications of the anti-CD44 mAb could significantly inhibit donor-reactive CD4(+) memory T cells from rejecting grafts via a Th1-dependent pathway, but xenoreactive CD4(+) memory T cells can avoid the effects of anti-CD44 mAb to reject islet xenografts via a Th2-dependent pathway.

Donor-reactive memory T cells are known to accelerate allograft rejection; in our previous study, we reported that combined monoclonal antibodies (mAbs) could prolong islet allograft survival in alloantigen-primed mice. In this study, we examine the effects of donor-reactive memory T cells on the xenograft survival and methods to prolong the islet graft survival.To collect donor-reactive T cells, we performed full-thickness rat skin xenografting on BALB/c mice and isolated the T cells from the mice after 6-8 weeks. These cells were then adoptively transferred to syngenic mice 1 day before rat-to-mouse islet transplantation. Three experimental groups were established in the adoptive transfer model: recipient mice treated with isotype mAbs (isotype group); mice treated with anti-CD40L mAb (anti-CD40L group); and mice treated with anti-CD40L, anti-OX40L, and anti-CD122 mAbs (3-combined group).Lewis rat islet xenografts transplanted in naïve mice showed a mean survival time (MST) of 12.8 days, while the graft rejection was accelerated if the recipient mice were treated with adoptively transferred donor-reactive T cells (MST, 8.67 days). Treatment with anti-CD40L mb could not reverse the accelerated rejection (MST, 9.3 days). However, when anti-CD40L mb was combined with anti-OX40L and anti-CD122 mAbs, there was a considerable increase in the MST, which was 72.2 days. Compared to the isotype group, the 3-combined group had significantly lesser proportion of memory T cells and greater proportion of regulatory T cells (Tregs) in the spleen. Meanwhile, in the 3-combined group, the production of anti-rat antibodies was markedly inhibited. Treatment with a combination of antibodies could significantly reverse the accelerated rejection mediated by donor-reactive memory T cells by inhibiting cellular and humoral immune responses.