Cd22-KO Mouse

CD22, also known as Siglec-2 (Sialic acid-binding Ig-like lectin 2), is a canonical B-cell receptor. It is involved in regulating immune responses, especially in the context of B-cell function and microglial activity. In B-cells, it modulates signaling pathways related to cell activation and differentiation. In microglia, it has been shown to be a key regulator of phagocytosis and inflammatory activity [1,2].

In a mouse model of intracerebral hemorrhage (ICH), upregulation of CD22 predominantly occurred in microglia. Antibody blockade of CD22 led to reduced neurological deficits, brain lesion and hematoma volume, accompanied by decreased inflammatory activity, increased expression of alternative activation markers, and enhanced phagocytosis in microglia. These effects were ablated when microglia were depleted, suggesting CD22's key role in microglial-mediated responses after ICH [1]. In aged mice, CD22 was identified as a negative regulator of microglial phagocytosis through CRISPR-Cas9 knockout screens. Blockade of CD22 restored homeostatic microglial phagocytosis and improved cognitive function in aged mice [2]. In the context of B-cell malignancies, targeting CD22 with chimeric antigen receptor (CAR) T-cells has shown promise. CD22-CAR T-cells induced remission in B-cell acute lymphoblastic leukemia (B-ALL), including cases naive or resistant to CD19-targeted CAR immunotherapy [4]. Dual-targeted (CD19/CD22) and trispecific (CD19-CD20-CD22) CAR-T-cell therapies also demonstrated anti-tumor activity against B-cell malignancies, preventing antigen-loss-mediated relapse [3,5,6,7,8].

In conclusion, CD22 plays a crucial role in microglial function, affecting neuroinflammation and cognitive function in the context of acute brain injury and aging. In B-cell malignancies, CD22 is a valuable target for immunotherapy. Gene-knockout and antibody-blockade models have been instrumental in revealing these functions, providing insights into potential therapeutic strategies for treating neurological disorders and B-cell cancers.

References:

1. Ren, Honglei, Pan, Yan, Wang, Danni, Shi, Fu-Dong, Liu, Qiang. 2023. CD22 blockade modulates microglia activity to suppress neuroinflammation following intracerebral hemorrhage. In Pharmacological research, 196, 106912. doi:10.1016/j.phrs.2023.106912. https://pubmed.ncbi.nlm.nih.gov/37696483/

2. Pluvinage, John V, Haney, Michael S, Smith, Benjamin A H, Bassik, Michael C, Wyss-Coray, Tony. 2019. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. In Nature, 568, 187-192. doi:10.1038/s41586-019-1088-4. https://pubmed.ncbi.nlm.nih.gov/30944478/

3. Hu, Yongxian, Zhou, Yali, Zhang, Mingming, Ren, Jiangtao, Huang, He. 2021. CRISPR/Cas9-Engineered Universal CD19/CD22 Dual-Targeted CAR-T Cell Therapy for Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia. In Clinical cancer research : an official journal of the American Association for Cancer Research, 27, 2764-2772. doi:10.1158/1078-0432.CCR-20-3863. https://pubmed.ncbi.nlm.nih.gov/33627493/

4. Fry, Terry J, Shah, Nirali N, Orentas, Rimas J, Lee, Daniel W, Mackall, Crystal L. 2017. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. In Nature medicine, 24, 20-28. doi:10.1038/nm.4441. https://pubmed.ncbi.nlm.nih.gov/29155426/

5. Schneider, Dina, Xiong, Ying, Wu, Darong, Orentas, Rimas J, Dropulić, Boro. . Trispecific CD19-CD20-CD22-targeting duoCAR-T cells eliminate antigen-heterogeneous B cell tumors in preclinical models. In Science translational medicine, 13, . doi:10.1126/scitranslmed.abc6401. https://pubmed.ncbi.nlm.nih.gov/33762438/

6. Spiegel, Jay Y, Patel, Shabnum, Muffly, Lori, Mackall, Crystal L, Miklos, David B. 2021. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. In Nature medicine, 27, 1419-1431. doi:10.1038/s41591-021-01436-0. https://pubmed.ncbi.nlm.nih.gov/34312556/

7. Liu, Shuangyou, Deng, Biping, Yin, Zhichao, Chang, Alex H, Tong, Chunrong. 2021. Combination of CD19 and CD22 CAR-T cell therapy in relapsed B-cell acute lymphoblastic leukemia after allogeneic transplantation. In American journal of hematology, 96, 671-679. doi:10.1002/ajh.26160. https://pubmed.ncbi.nlm.nih.gov/33725422/

8. Dai, Hanren, Wu, Zhiqiang, Jia, Hejin, Wang, Yao, Han, Weidong. 2020. Bispecific CAR-T cells targeting both CD19 and CD22 for therapy of adults with relapsed or refractory B cell acute lymphoblastic leukemia. In Journal of hematology & oncology, 13, 30. doi:10.1186/s13045-020-00856-8. https://pubmed.ncbi.nlm.nih.gov/32245502/