Monotherapy With Anti-CD70 Antibody Causes Long-Term Mouse Cardiac Allograft Acceptance With Induction of Tolerogenic Dendritic Cells.

Jing Zhao,Piotr Zabrocki,Masayuki Fujino,Naotsugu Ichimaru,Nobuko Tokuda,Hans De Haard,Weitao Que,Xiao-Kang Li,Wen-Zhi Guo,Xiaoxiao Du,Hisashi Ueta,Norio Nonomura

doi:10.3389/fimmu.2020.555996

Abstract

Allograft rejection has been an obstacle for the long-term survival of patients. CD70, a tumor necrosis factor (TNF) family member critically expressed on antigen-presenting cells and strongly but transiently up-regulated during lymphocyte activation, represents an important co-stimulatory molecule that induces effective T cell responses. We used a mouse heterotopic cardiac transplantation model to evaluate the effects of monotherapy with the antibody targeting mouse CD70 (FR70) on transplantation tolerance and its immunoregulatory activity. FR70-treated C3H recipient mice permanently accepted B6 fully mismatched cardiac allografts. Consistent with the graft survival, the infiltration of CD8+ T cells in the graft was reduced, dendritic cells were differentiated into a tolerogenic status, and the number of regulatory T cells was elevated both in the graft and the recipient’s spleen. In addition, naïve C3H given an adoptive transfer of spleen cells from the primary recipients with FR70 treatment accepted a heart graft from a matching B6 donor but not third-party BALB/c mice. Our findings show that treatment with FR70 induced regulatory cells and inhibited cytotoxic T cell proliferation, which led to long-term acceptance of mouse cardiac allografts. These findings highlight the potential role of anti-CD70 antibodies as a clinically effective treatment for allograft rejection.

Highlights

Significant breakthroughs have been made in regard to the shortterm graft survival over the last few decades, but improving the long-term graft survival still remains a challenge
When we evaluated the expression of CD40, CD80, CD86 and major histocompatibility complex (MHC) class II proteins in CD11c+CD11b+ cells by flow cytometry (FCM), we found that the expression of all of these proteins was lower in the FR70-treated recipients in comparison to the control group treated with the isotype antibody (Figure 3B)
The observed effects appeared to be long-lasting for the PD-L1 and CD86 expression in spleen, since the same significant change in the expression was still present at POD100 (Figure 3B). In agreement with these results, we found that the mRNA levels of CD40, CD80, and CD86 and MHC class II antigens were significantly lower in Graft-infiltrating lymphocytes (GILs) and/or spleen cells (SPCs) isolated from the FR70-treated group at POD7 and/or POD60 and 100 than in those isolated from the isotype control group at POD7 (Figure 3C)

Summary

Introduction

Significant breakthroughs have been made in regard to the shortterm graft survival over the last few decades, but improving the long-term graft survival still remains a challenge. AntiCD70 monoclonal antibody (mAb) administered in combination with an anti-CD154/LFA-1 mAbs regimen during primary transplantation alleviated the accelerated rejection mediated by memory T cells [4]. In a memory T cell-based adoptive mouse model, the combination of four antibodies against CD44, CD70, CD40L, and LFA-1 significantly inhibited the proliferation of memory T cells ex vivo but failed to induce long-lived heart allograft acceptance in vivo [5]. The transgenic expression of CD70 on resting DCs is sufficient to provide CD8+ T cells with immunity, whereas its blockade averts CD8+ T cell priming in lymphocytic choriomeningitis virus infection [8, 9, 11, 12]. In cancer vaccine therapy, blocking CD70 markedly reduced the effect of CD4+ T cell-mediated aid, such that CD70 blockade almost completely abolished the therapeutic effect of the “Help” vaccine [14]

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Results

Conclusion