- Spleen tyrosine kinase (Syk) is a novel pharmaceutical target in the treatment of allergic, autoimmune and neoplastic diseases. Previous studies have shown that Syk signaling plays a key role in regulating the lymphohematopoietic system. These observations prompted us to investigate whether Syk’s inhibition promoted immunotoxicity.
- In a series of studies, rats were given orally R406 at doses up to and including 100 mg / kg / day (or its prodrug R788 at doses up to and including 100 mg / kg / day, reduced to 50 mg / day). ). kg / day for women after passing MTD), a strong Syk inhibitor, twice daily for 28 days.
- Oltre alle valutazioni tossicologiche standard, sono stati eseguiti test di immunofenotipizzazione citometrica a flusso e di risposta immunitaria umorale misurando i livelli di anticorpi IgM e IgG anti – KLH . Altri studi di immunotossicità includevano tre modelli di resistenza dell’ospite in topi Balb/c femmine per determinare ulteriormente gli effetti di R406 sull’immunità innata e acquisita.
- Dopo il trattamento con R406, negli studi sui ratti sono stati osservati gli effetti immunomodulatori attesi (ad es. diminuzione del peso del timo e della milza, perdita di cellule del midollo osseo e diminuzione della conta dei linfociti, inclusi i linfociti T e B). Questi cambiamenti si sono generalmente risolti dopo un periodo di recupero di 14 giorni senza trattamento . KLH challenge nei ratti non ha mostrato effetti avversi sulla risposta IgG o IgM . R788/406, somministrato per via orale a dosi fino a 80 mg/kg/die inclusi per 28 giorni, non ha influenzato la clearance batterica o virale nei modelli di resistenza murina rispettivamente di Listeria, streptococco o ospiti dell’influenza.
- Ciò era correlato a precedenti test di funzionalità dei macrofagi e dei neutrofili in vitro (valutazione di ioni migratori, fagocitosi, scoppio ossidativo e attività battericida) che hanno mostrato che l’ R406 non ha influenzato negativamente la funzione dei macrofagi o dei neutrofili nelle risposte immunitarie innate. Presi insieme, questi risultati mostrano che l’ R406 ha un’immunotossicità funzionale minima nonostante i suoi effetti linfocitopenici, suggerendo che l’inibizione di Syk potrebbe non portare a effetti avversi inaccettabili basati sui meccanismi.
Valutazione dell’immunotossicità per il nuovo inibitore della tirosin-chinasi della milza R406.
-
- Cdna 8Spleen tirosin chinasi (Syk) è un nuovo target farmaceutico nel trattamento delle malattie allergiche, autoimmuni e cancerose. Precedenti studi hanno dimostrato che la segnalazione Syk svolge un ruolo chiave nella regolazione del sistema linfoematopoietico.
- Queste osservazioni ci hanno spinto a indagare se l’inibizione di Syk promuovesse l’immunotossicità. In una serie di studi , ai ratti è stato somministrato per via orale R406 a dosi fino a 100 mg/kg/die inclusi (o il suo profarmaco R788 a dosi fino a 100 mg/kg/die inclusi, ridotti a 50 mg/die). kg/die per le donne dopo aver superato la MTD), un forte inibitore Syk, due volte al giorno per 28 giorni.
- In addition to standard toxicological assessments , flow cytometric immunophenotyping and humoral immune response tests were performed by measuring levels of anti – KLH IgM and IgG antibodies . Other immunotoxicity studies included three host resistance models in female Balb / c mice to further determine the effects of R406 on innate and acquired immunity.
- After treatment with R406, the expected immunomodulatory effects (e.g. decreased thymus and spleen weight, loss of bone marrow cells and decreased lymphocyte counts, including T and B lymphocytes) were observed in rat studies. .
- These changes generally resolved during the 14-day treatment-free recovery period. KLH challenge in rats showed no adverse effects on IgG or IgM response . R788 / 406, administered orally at doses up to and including 80 mg / kg / day for 28 days, did not affect bacterial or viral clearance in mouse resistance models of Listeria, streptococcus or influenza hosts, respectively.
- This was related to previous in vitro macrophage and neutrophil function tests (evaluation of migratory ions, phagocytosis, oxidative burst and bactericidal activity) which showed that R406 did not adversely affect macrophage or neutrophil function in immune responses. innate.
- Taken together, these results show that R406 has minimal functional immunotoxicity despite its lymphocytopenic effects, suggesting that Syk inhibition may not lead to unacceptable mechanism-based adverse effects.
To test whether IL-10 acts as an autocrine or paracrine growth factor for Ly-1 B cells, we treated mice continuously from birth to 8 weeks of age with a rat monoclonal IgM antibody that specifically neutralizes IL-10. murine. Mice treated in this manner were deprived of peritoneal Ly-1 B cells, contained significantly reduced serum levels of immunoglobulin M, and were unable to generate significant in vivo antibody responses to intraperitoneal injection of alpha 1,3-dextran or phosphorylcholine, antigens , for which specific B cells are found in the subset of Ly-1 B cells.
In contrast, spleen B cells from conventional anti -IL-10-treated mice were normal with respect to total number, phenotype, and in vitro response to B cell mitogens and trinitrophenyl hemocyanin antigen (TNP- KLH ) from thymus-dependent keyhole patella. ).
The mechanism of Ly-1 B cell depletion appears to be related to increased levels of endogenous interferon gamma (IFN-gamma) in mice treated with anti-IL-10 because they co-administered anti-IFN-gamma sub anti – IL. – 10 neutralizing antibodies . alli restored the number of Ly-1 B cells residing in the peritoneum of these mice.
In contrast, spleen B cells from conventional anti -IL-10-treated mice were normal with respect to total number, phenotype, and in vitro response to B cell mitogens and trinitrophenyl hemocyanin antigen (TNP- KLH ) from thymus-dependent keyhole patella. ).
The mechanism of Ly-1 B cell depletion appears to be related to increased levels of endogenous interferon gamma (IFN-gamma) in mice treated with anti-IL-10 because they co-administered anti-IFN-gamma sub anti – IL. – 10 neutralizing antibodies . alli restored the number of Ly-1 B cells residing in the peritoneum of these mice. These results suggest that IL-10 is a growth regulator of Ly-1 B cells and identify a procedure for specific depletion of Ly-1 B cells, thus allowing further evaluation of the role of these cells in the immune system.
Anti-Flag antibody (KLH)
STJ98077
100 µl
280.8 EUR
Anti-BNP antibody (KLH)
STJ97879
100 µl
280.8 EUR
Anti-BNP antibody (KLH)
STJ97880
100 µl
280.8 EUR
Anti-BNP antibody (KLH)
STJ97881
100 µl
280.8 EUR
Anti-Calnexin antibody (KLH)
STJ97891
100 µl
280.8 EUR
Anti-Calregulin antibody (KLH)
STJ97892
100 µl
280.8 EUR
Anti-cAMP antibody (KLH)
STJ97893
100 µl
280.8 EUR
Anti-CD20 antibody (KLH)
STJ97914
100 µl
280.8 EUR
Anti-Clenbuterol antibody (KLH)
STJ97960
100 µl
280.8 EUR
Bovine Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-b-48T
48T
547.2 EUR
Bovine Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-b-96T
96T
708 EUR
Chicken Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Ch-48T
48T
511.2 EUR
Chicken Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Ch-96T
96T
658.8 EUR
Human Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Hu-48T
48T
484.8 EUR
Human Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Hu-96T
96T
621.6 EUR
Mouse Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Mu-48T
48T
493.2 EUR
Mouse Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Mu-96T
96T
633.6 EUR
Rabbit Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Rb-48T
48T
609.6 EUR
Rabbit Immunoglobulin M (IgM) ELISA Kit
DLR-IgM-Rb-96T
96T
793.2 EUR
Bovine Immunoglobulin M (IgM) ELISA Kit
RD-IgM-b-48Tests
48 Tests
543.6 EUR
Bovine Immunoglobulin M (IgM) ELISA Kit
RD-IgM-b-96Tests
96 Tests
750 EUR
Bovine Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-b-48Tests
48 Tests
567.6 EUR
Bovine Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-b-96Tests
96 Tests
784.8 EUR
Chicken Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Ch-48Tests
48 Tests
524.4 EUR
Chicken Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Ch-96Tests
96 Tests
723.6 EUR
Human Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Hu-48Tests
48 Tests
493.2 EUR
Human Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Hu-96Tests
96 Tests
678 EUR
Mouse Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Mu-48Tests
48 Tests
502.8 EUR
Mouse Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Mu-96Tests
96 Tests
693.6 EUR
Rabbit Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Rb-48Tests
48 Tests
640.8 EUR
Rabbit Immunoglobulin M (IgM) ELISA Kit
RDR-IgM-Rb-96Tests
96 Tests
890.4 EUR
Human Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative
700-145-KLM
1 Kit
927.6 EUR
Mouse Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative
700-155-VAM
1 Kit
854.4 EUR
Monkey Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative
700-180-KLM
1 Kit
927.6 EUR
Canine Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative
700-190-KLM
1 Kit
927.6 EUR
Rat anti Mouse IgM
41R-1116
100 ug
318 EUR
Mouse anti Rat IgM
41R-1122
100 ug
318 EUR
Mouse anti Rat IgM
41R-1123
100 ug
318 EUR
Rabbit anti Rat IgM
40C-CB1264
2 mg
342 EUR
Goat anti Rat IgM
40C-CB1271
1 mg
435.6 EUR
Rat(anti-CMV IgM)
QY-E11747
96T
448.8 EUR
Human keyhole limpet hemocyanin(KLH) antibody(IgM) ELISA Kit
CSB-E16534h-24T
1 plate of 24 wells
198 EUR
Human keyhole limpet hemocyanin(KLH) antibody(IgM) ELISA Kit
1-CSB-E16534h
Mouse keyhole limpet hemocyanin (KLH) antibody (IgM) ELISA kit
CSB-E13375m-24T
1 plate of 24 wells
198 EUR
Mouse keyhole limpet hemocyanin (KLH) antibody (IgM) ELISA kit
1-CSB-E13375m
Rat KLH ELISA Kit
ERK0075
96Tests
625.2 EUR
Lyophilized Exosome Standards
ExoA375
100 μg
364.2 EUR
Lyophilized Exosome Standards
ExoHT29
100 μg
364.2 EUR
Lyophilized Exosome Standards
ExoMCF7
100 μg
364.2 EUR
Lyophilized Exosome Standards
ExoPC3
100 μg
364.2 EUR
Lyophilized Exosome Standards
ExoPLASMA
100 μg
364.2 EUR
Lyophilized Exosome Standards
ExoUrine
100 μg
364.2 EUR
Density Standards 6ml
DEN1012
PK10
69.31 EUR
Chlorine meter standards
WAT1076
EACH
269.04 EUR
Human Anti-Keyhole limpet hemocyanin (KLH) IgG+IgM ELISA Kit, 96 tests, Quantitative
700-135-KGM
1 kit
927.6 EUR
Bovine/Cow Anti-Keyhole limpet hemocyanin (KLH) IgM ELISA Kit, 96 tests, Quantitative
700-205-KLM
1 Kit
854.4 EUR
Anti-Myc-tag antibody (KLH)
STJ90105
200 µl
236.4 EUR
Anti-His-tag antibody (KLH)
STJ90106
200 µl
236.4 EUR
Anti-HA-tag antibody (KLH)
STJ90107
200 µl
236.4 EUR
Anti-FLAG-tag antibody (KLH)
STJ90108
200 µl
236.4 EUR
Anti-E alpha antibody (KLH)
STJ98053
100 µl
280.8 EUR
Anti-Ki-67 antibody (KLH)
STJ98194
100 µl
280.8 EUR
Anti-Ki-67 antibody (KLH)
STJ98195
100 µl
280.8 EUR
Anti-PARP-1 antibody (KLH)
STJ98308
100 µl
280.8 EUR
Anti-Actin beta antibody (KLH)
STJ97814
100 µl
280.8 EUR
Anti-Bcl-2 antibody (KLH)
STJ97860
100 µl
280.8 EUR
Custom production of antibodies in 5 Rats using customer supplied antigen (std 63 days protocol)
RAT-5
1
1365.6 EUR
Rabbit anti Rat IgM (FITC)
43C-CB1265
1.5 mg
346.8 EUR
Rabbit anti Rat IgM (rhodamine)
43C-CB1266
1.5 mg
363.6 EUR
Rabbit anti Rat IgM (biotin)
43C-CB1268
1.5 mg
441.6 EUR
Rabbit anti Rat IgM (HRP)
43C-CB1269
1.5 mg
478.8 EUR
Goat anti Rat IgM (FITC)
43C-CB1272
1 mg
436.8 EUR
Goat anti Rat IgM (rhodamine)
43C-CB1273
1 mg
482.4 EUR
Goat anti Rat IgM (biotin)
43C-CB1275
1 mg
466.8 EUR
Goat anti Rat IgM (HRP)
43C-CB1276
1 mg
534 EUR
Mouse anti Rat IgM (HRP)
43R-1632
100 ug
338.4 EUR
Mouse anti Rat IgM (HRP)
43R-1633
100 ug
338.4 EUR
Goat anti-Rat IgM Antibody
abx401442-05mg
0.5 mg
444 EUR
Goat Anti-Rat IgM-AP
LF-SA8011AP
1.0 ml
423.6 EUR
Goat Anti-Rat IgM-BIOT
LF-SA8011B
1.0 mg
374.4 EUR
Goat Anti-Rat IgM-FITC
LF-SA8011F
1.0 mg
328.8 EUR
Goat Anti-Rat IgM-HRP
LF-SA8011H
1.0 ml
336 EUR
Goat Anti-Rat IgM-PE
LF-SA8011P
0.5 mg
524.4 EUR
Goat Anti-Rat IgM-TXRD
LF-SA8011T
1.0 mg
294 EUR
Goat Anti-Rat IgM-TRITC
LF-SA8011TR
1.0 mg
319.2 EUR
Goat Anti-Rat IgM-UNLB
LF-SA8011U
1.0 mg
313.2 EUR
Chloramphenicol [KLH]
DAG2974K
1mg
1170 EUR
Amoxicillin [KLH]
DAG4477
0.5mg
1248 EUR
Ampicillin [KLH]
DAG4478
0.5mg
1248 EUR
Apramycin [KLH]
DAG4479
0.5mg
1248 EUR
Bacitracin [KLH]
DAG4480
0.5ml
1170 EUR
Cloxacillin [KLH]
DAG4483
0.5mg
1248 EUR
Gentamicin [KLH]
DAG4484
1mg
1248 EUR
Neomycin [KLH]
DAG4486
0.5ml
1248 EUR
Streptomycin [KLH]
DAG4488
0.5ml
1482 EUR
Melamine [KLH]
DAG4492
1mg
1170 EUR
Ractopamine [KLH]
DAGA-001K
1mg
1170 EUR
Salbutamol [KLH]
DAGA-002K
1mg
1248 EUR
Clenbuterol [KLH]
DAGA-003K
1mg
1248 EUR
Pb2+ [KLH]
DAGA-005K
1mg
1560 EUR
Cd2+ [KLH]
DAGA-006K
1mg
1263.6 EUR
Hg2+ [KLH]
DAGA-007K
1mg
1263.6 EUR
Cu2+ [KLH]
DAGA-008K
1mg
1326 EUR
Ochratoxin [KLH]
DAGA-012K
1mg
1326 EUR
Zearalenone [KLH]
DAGA-013K
1mg
1014 EUR
Fumonisin [KLH]
DAGA-014K
1mg
1201.2 EUR
Deoxynivalenol [KLH]
DAGA-016K
500ul
1482 EUR
Sterigmatocystin [KLH]
DAGA-017K
1mg
1326 EUR
Methyltestosterone [KLH]
DAGA-020K
1mg
1248 EUR
Testosterone [KLH]
DAGA-021K
1mg
1232.4 EUR
Medroxyprogesterone [KLH]
DAGA-022K
1mg
1263.6 EUR
Progesterone [KLH]
DAGA-023K
1mg
1326 EUR
Hexadecadrol [KLH]
DAGA-024K
1mg
1248 EUR
Diethylstilbestrol [KLH]
DAGA-025K
1mg
1326 EUR
Hexoestrolum [KLH]
DAGA-026K
1mg
1248 EUR
Hydrocortisone [KLH]
DAGA-027K
1mg
1248 EUR
Estradiol [KLH]
DAGA-028K
1mg
1170 EUR
Nonylphenol [KLH]
DAGA-032K
1mg
1248 EUR
Ribavirin [KLH]
DAGA-033K
1mg
1294.8 EUR
Amantadine [KLH]
DAGA-034K
1mg
1294.8 EUR
Sulfadiazine [KLH]
DAGA-035K
1mg
1294.8 EUR
Sulfaquinoxaline [KLH]
DAGA-036K
1mg
1170 EUR
Sulfamethazine [KLH]
DAGA-037K
1mg
1014 EUR
Sulfadimethoxine [KLH]
DAGA-038K
1mg
1326 EUR
Trimethoprim [KLH]
DAGA-039K
1mg
1326 EUR
Chloramphenicol [KLH]
DAGA-040K
1mg
1248 EUR
Florfenicol [KLH]
DAGA-042K
1mg
1014 EUR
Kanamycin [KLH]
DAGA-044K
1mg
1170 EUR
Neomycin [KLH]
DAGA-045K
1mg
1326 EUR
Lincomycin [KLH]
DAGA-046K
1mg
1482 EUR
Pirlimycin [KLH]
DAGA-047K
1mg
1326 EUR
Erythrocin [KLH]
DAGA-048K
1mg
1014 EUR
Spectinomycin [KLH]
DAGA-049K
1mg
1294.8 EUR
Avermectin [KLH]
DAGA-050K
1mg
1248 EUR
Tylosin [KLH]
DAGA-051K
1mg
1326 EUR
Tilmicosin [KLH]
DAGA-052K
1mg
1482 EUR
Vancomycin [KLH]
DAGA-053K
1mg
1248 EUR
Salinomycin [KLH]
DAGA-054K
1mg
1482 EUR
Monensin [KLH]
DAGA-055K
1mg
1248 EUR
Albendazole [KLH]
DAGA-056K
1mg
1324.8 EUR
Natamycin [KLH]
DAGA-057K
1mg
1248 EUR
Metronidazole [KLH]
DAGA-058K
1mg
1248 EUR
Tetracycline [KLH]
DAGA-059K
1mg
1014 EUR
Olaquindox [KLH]
DAGA-060K
1mg
1326 EUR
Ciprofloxacin [KLH]
DAGA-063K
1mg
1404 EUR
Sarafloxacin [KLH]
DAGA-064K
1mg
1294.8 EUR
Ofloxacin [KLH]
DAGA-065K
1mg
1294.8 EUR
Enrofloxacin [KLH]
DAGA-066K
1mg
1248 EUR
Ceftiofur [KLH]
DAGA-068K
1mg
1404 EUR
Cefquinome [KLH]
DAGA-069K
1mg
1232.4 EUR
Fluoroquinolones [KLH]
DAGA-070K
1mg
1014 EUR
Sulfanilamides [KLH]
DAGA-071K
1mg
1014 EUR
Biotin [KLH]
DAGA-074K
1mg
1248 EUR
Erythrosine [KLH]
DAGA-076K
1mg
1248 EUR
Chrysoidine [KLH]
DAGA-077K
1mg
1248 EUR
Tartrazine [KLH]
DAGA-079K
1mg
1232.4 EUR
Sudan [KLH]
DAGA-081K
1mg
1326 EUR
Carbendazim [KLH]
DAGA-082K
1mg
1404 EUR
Chlorothalonil [KLH]
DAGA-083K
1mg
1248 EUR
Chlorpyrifos [KLH]
DAGA-085K
1mg
1248 EUR
Carbaryl [KLH]
DAGA-086K
1mg
1248 EUR
Acetochlor [KLH]
DAGA-087K
1mg
1248 EUR
Acetamiprid [KLH]
DAGA-088K
1mg
1248 EUR
Imidacloprid [KLH]
DAGA-089K
1mg
1170 EUR
Fenpropathrin [KLH]
DAGA-090K
1mg
1170 EUR
Pentachlorophenol [KLH]
DAGA-093K
1mg
1170 EUR
Nitrazepam [KLH]
DAGA-097K
1mg
1404 EUR
Clonazepam [KLH]
DAGA-098K
1mg
1248 EUR
Diazepam [KLH]
DAGA-099K
1mg
1248 EUR
Dihydrochlorothiazide [KLH]
DAGA-100K
1mg
1248 EUR
Benzothiazinone [KLH]
DAGA-101K
1mg
1248 EUR
Benzothiazine [KLH]
DAGA-102K
1mg
1248 EUR
Mercaptobenzothiazole [KLH]
DAGA-104K
1mg
1092 EUR
Imazalil [KLH]
DAGA-105K
1mg
1201.2 EUR
Benzophenone [KLH]
DAGA-106K
1mg
1248 EUR
Acrylamide [KLH]
DAGA-110K
1mg
1248 EUR
Gossypol [KLH]
DAGA-118K
1mg
1248 EUR
KLH antibody
70R-30550
1 ml
224.4 EUR
KLH Antibody
48158-100ul
100ul
399.6 EUR
KLH Antibody
48158-50ul
50ul
286.8 EUR
These results suggest that IL-10 is a growth regulator of Ly-1 B cells and identify a procedure for specific depletion of Ly-1 B cells, thus allowing further evaluation of the role of these cells in the immune system.