Kidney Week

Abstract: SA-OR20

Targeting CD153+PD-1+CD4+ Senescence-Associated T Cells Ameliorates Kidney Damage by Attenuating Tertiary Lymphoid Structure Formation

Session Information

• CKD: New Insights into Mechanisms and Treatment Strategies
  October 26, 2024 | Location: Room 24, Convention Center
  Abstract Time: 04:40 PM - 04:50 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Taniguchi, Keisuke, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan

Keisuke Taniguchi, MD

• Yoshikawa, Takahisa, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan

Takahisa Yoshikawa, MD, PhD

• Sato, Yuki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan

Yuki Sato, MD, PhD

• Kohno, Kenji, Hyogo Kenritsu Daigaku, Kobe, Hyogo, Japan

Kenji Kohno, PhD

• Takahashi, Satoru, Tsukuba Daigaku, Tsukuba, Ibaraki, Japan

Satoru Takahashi, MD, PhD

• Nagata, Satoshi, Epitope Science Co.,Ltd., Ibaraki, Osaka, Japan

Satoshi Nagata, PhD

• Kamada, Haruhiko, Epitope Science Co.,Ltd., Ibaraki, Osaka, Japan

Haruhiko Kamada, PhD

• Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto, Japan

Motoko Yanagita, MD, PhD

Background

We previously reported that tertiary lymphoid structures (TLSs) develop in the aged injured kidneys, with tissue maladaptive repair. In addition, we showed that the interactions between senescence-associated T cells (SA-T cells) and age-associated B cells (ABCs) via CD153-CD30 signaling are essential for TLS expansion. However, it remained unclear whether the intervention targeting SA-T cells can improve kidney prognosis.

Methods

CD153 knocked-in (CD153KI) mice, expressing enhanced green fluorescent protein (EGFP) and human diphtheria toxin receptor (hDTR) downstream of the CD153 promoter, were generated and subjected to ischemia-reperfusion injury (IRI), followed by DT administration. In addition, we made a mouse chimeric recombinant antibody (mcRM153) by using an antibody variable domain derived from the commercially available rat-derived anti-mouse CD153 antibody (RM153) and administered it to aged C57BL/6J mice after renal IRI. In both models, injured kidneys and spleens were analyzed by flow cytometry, immunostaining, in situ hybridization, and quantitative PCR.

Results

In the aged CD153KI mice, EGFP and hDTR-coexpressing T cells were identified in the spleens and within renal TLSs. Flow cytometry revealed that the majority of SA-T cells and smaller populations of CD4+ memory T cells expressed EGFP in the spleen and kidney, but other types of immune cells did not. One day after the first DT administration, the number of SA-T cells was reduced in the spleen and renal TLSs. Following the decrease in SA-T cells, the expression of chemokines, such as CCL19 and CXCL9, by proinflammatory fibroblasts within TLSs decreased by day 3, and TLSs were almost completely diminished by day 7. We also found that mcRM153 markedly reduced SA-T cells in the kidneys and spleen, significantly suppressed TLS formation, and reduced the VCAM1+ failed-repair proximal tubules and fibrosis in aged injured kidneys. In both models, the intervention reduced the proportion of germinal center B cells, but not ABCs.

Conclusion

Interventions targeting CD153 inhibit the formation of TLSs, ameliorate kidney damage, and may be therapeutic for CKD.

Funding

• Commercial Support – Boehringer Ingelheim