The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities.
JAK3 is a cytoplasmic tyrosine kinase with limited tissue expression but is readily found in activated T cells. Patients lacking JAK3 are immune compromised, suggesting that JAK3 represents a therapeutic target for immunosuppression. Herein, we show that a Mannich base, NC1153, blocked IL-2-induced activation of JAK3 and its downstream substrates STAT5a/b more effectively than activation of the closely related prolactin-induced JAK2 or TNF-alpha-driven NF-kappaB. In addition, NC1153 failed to inhibit several other enzymes, including growth factor receptor tyrosine kinases, Src family members, and serine/threonine protein kinases. Although NC1153 inhibited proliferation of normal human T cells challenged with IL-2, IL-4, or IL-7, it did not block T cells void of JAK3. In vivo, a 14-day oral therapy with NC1153 significantly extended survival of MHC/non-MHC mismatched rat kidney allografts, whereas a 90-day therapy induced transplantation tolerance (>200 days). Although NC1153 acted synergistically with cyclosporin A (CsA) to prolong allograft survival, it was not nephrotoxic, myelotoxic, or lipotoxic and did not increase CsA-induced nephrotoxicity. In contrast to CsA, NC1153 was not metabolized by cytochrome P450 3A4. Thus, NC1153 prolongs allograft survival without several toxic effects associated with current immunosuppressive drugs.
Stepkowski
Stanislaw M
SM
Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas Medical School at Houston, Houston, TX 77030, USA.
Kao
Judy
J
Wang
Mou-Er
ME
Tejpal
Neelam
N
Podder
Hemangshu
H
Furian
Lucrezia
L
Dimmock
Jonathan
J
Jha
Amitabh
A
Das
Umashankar
U
Kahan
Barry D
BD
Kirken
Robert A
RA
D000818:Animals; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000502:physiology; D053616:Janus Kinase 3; D016030:Kidney Transplantation; D008352:Mannich Bases / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D007376:Interleukin-2; C507936:Jak3 protein, rat; D008352:Mannich Bases; C503557:NC 1153; D016572:Cyclosporine; D011505:Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3