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Depletion of PD-1-positive cells ameliorates autoimmune disease

Zhao, P;Wang, P;Dong, S;Zhou, Z;Cao, Y;Yagita, H;He, X;Zheng, SG;Fisher, SJ;Fujinami, RS;Chen, M;
Product: Pertussis Toxin from B. pertussis, Lyophilized in Buffer

Targeted suppression of autoimmune diseases without collateral suppression of normal immunity remains an elusive yet clinically important goal. Targeted blockade of programmed-cell-death-protein-1 (PD-1)-an immune checkpoint factor expressed by activated T cells and B cells-is an efficacious therapy for potentiating immune activation against tumours. Here we show that an immunotoxin consisting of an anti-PD-1 single-chain variable fragment, an albumin-binding domain and Pseudomonas exotoxin targeting PD-1-expressing cells, selectively recognizes and induces the killing of the cells. Administration of the immunotoxin to mouse models of autoimmune diabetes delays disease onset, and its administration in mice paralysed by experimental autoimmune encephalomyelitis ameliorates symptoms. In all mouse models, the immunotoxin reduced the numbers of PD-1-expressing cells, of total T cells and of cells of an autoreactive T-cell clone found in inflamed organs, while maintaining active adaptive immunity, as evidenced by full-strength immune responses to vaccinations. The targeted depletion of PD-1-expressing cells contingent to the preservation of adaptive immunity might be effective in the treatment of a wide range of autoimmune diseases.

PubMed ID: 30952980
353235322019-04-172019-04-1710:30:1510:30:152019-04-192019-04-1913:57:4213:57:42Zhao, P;Wang, P;Dong, S;Zhou, Z;Cao, Y;Yagita, H;He, X;Zheng, SG;Fisher, SJ;Fujinami, RS;Chen, M;Zhao, P;Wang, P;Dong, S;Zhou, Z;Cao, Y;Yagita, H;He, X;Zheng, SG;Fisher, SJ;Fujinami, RS;Chen, M;20192019Depletion of PD-1-positive cells ameliorates autoimmune diseaseDepletion of PD-1-positive cells ameliorates autoimmune diseaseNature Biomedical EngineeringNature Biomedical Engineering292-305292-30533443095298030952980

Targeted suppression of autoimmune diseases without collateral suppression of normal immunity remains an elusive yet clinically important goal. Targeted blockade of programmed-cell-death-protein-1 (PD-1)-an immune checkpoint factor expressed by activated T cells and B cells-is an efficacious therapy for potentiating immune activation against tumours. Here we show that an immunotoxin consisting of an anti-PD-1 single-chain variable fragment, an albumin-binding domain and Pseudomonas exotoxin targeting PD-1-expressing cells, selectively recognizes and induces the killing of the cells. Administration of the immunotoxin to mouse models of autoimmune diabetes delays disease onset, and its administration in mice paralysed by experimental autoimmune encephalomyelitis ameliorates symptoms. In all mouse models, the immunotoxin reduced the numbers of PD-1-expressing cells, of total T cells and of cells of an autoreactive T-cell clone found in inflamed organs, while maintaining active adaptive immunity, as evidenced by full-strength immune responses to vaccinations. The targeted depletion of PD-1-expressing cells contingent to the preservation of adaptive immunity might be effective in the treatment of a wide range of autoimmune diseases.

Targeted suppression of autoimmune diseases without collateral suppression of normal immunity remains an elusive yet clinically important goal. Targeted blockade of programmed-cell-death-protein-1 (PD-1)-an immune checkpoint factor expressed by activated T cells and B cells-is an efficacious therapy for potentiating immune activation against tumours. Here we show that an immunotoxin consisting of an anti-PD-1 single-chain variable fragment, an albumin-binding domain and Pseudomonas exotoxin targeting PD-1-expressing cells, selectively recognizes and induces the killing of the cells. Administration of the immunotoxin to mouse models of autoimmune diabetes delays disease onset, and its administration in mice paralysed by experimental autoimmune encephalomyelitis ameliorates symptoms. In all mouse models, the immunotoxin reduced the numbers of PD-1-expressing cells, of total T cells and of cells of an autoreactive T-cell clone found in inflamed organs, while maintaining active adaptive immunity, as evidenced by full-strength immune responses to vaccinations. The targeted depletion of PD-1-expressing cells contingent to the preservation of adaptive immunity might be effective in the treatment of a wide range of autoimmune diseases.

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... The peptide was emulsified in 0.2 ml complete Freund’s adjuvant (CFA, Sigma). Four hours later, the mice were injected intraperitoneally with 200 ng pertussis toxin (List Biological Labs), and an additional 200 ng pertussis toxin 24 h later. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

... The peptide was emulsified in 0.2 ml complete Freund’s adjuvant (CFA, Sigma). Four hours later, the mice were injected intraperitoneally with 200 ng pertussis toxin (List Biological Labs), and an additional 200 ng pertussis toxin 24 h later. ...

Author did not specify which List Labs Pertussis Toxin was utilized.  List Labs provides Product #180 - Pertussis Toxin from B. pertussis, Lyophilized in Buffer and Product #181 - Pertussis Toxin from B. pertussis, Lyophilized (Salt-Free).

https://www.nature.com/articles/s41551-019-0360-0https://www.nature.com/articles/s41551-019-0360-02019-04-012019-04-0110.1038/s41551-019-0360-010.1038/s41551-019-0360-0Pertussis Toxin from B. pertussis, Lyophilized in BufferPertussis Toxin from B. pertussis, Lyophilized in Buffermingnan.chen@utah.edumingnan.chen@utah.eduActivated;Activation;Active;Adjuvant;Anti;Autoimmune;Binding;Biological;Cell;Chain;Depletion;Disease;Domain;Encephalomyelitis;Exotoxin;Experimental;Experimental Autoimmune Encephalomyelitis;Expressed;Factor;Fragment;List;List Biological;List Biological Labs;Mouse;Peptide;Pertussis;Positive;Protein;Selectively;T-cell;Toxin;Treatment;Nature Biomedical EngineeringActivated;Activation;Active;Adjuvant;Anti;Autoimmune;Binding;Biological;Cell;Chain;Depletion;Disease;Domain;Encephalomyelitis;Exotoxin;Experimental;Experimental Autoimmune Encephalomyelitis;Expressed;Factor;Fragment;List;List Biological;List Biological Labs;Mouse;Peptide;Pertussis;Positive;Protein;Selectively;T-cell;Toxin;Treatment;Nature Biomedical Engineering180180depletion-of-pd-1-positive-cells-amelioratesdepletion-of-pd-1-positive-cells-ameliorates