The Mannich Base NC1153 Promotes Long-Term Allograft Survival and Spares the Recipient from Multiple Toxicities

• Published in: Journal of Immunology Vol. 175; no. 7; pp. 4236 - 4246
• Main Authors: Stepkowski, Stanislaw M, Kao, Judy, Wang, Mou-Er, Tejpal, Neelam, Podder, Hemangshu, Furian, Lucrezia, Dimmock, Jonathan, Jha, Amitabh, Das, Umashankar, Kahan, Barry D, Kirken, Robert A
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.10.2005
• Subjects: Animals; Cell Line; Cyclosporine - pharmacology; Graft Survival - drug effects; Humans; Immunosuppressive Agents - pharmacology; Interleukin-2 - physiology; Janus Kinase 3; Kidney Transplantation; Mannich Bases - pharmacology; Phosphorylation - drug effects; Protein-Tyrosine Kinases - metabolism; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Spleen - cytology; Spleen - transplantation; Transplantation, Homologous
• ISSN: 0022-1767; 1550-6606; 1365-2567
• DOI: 10.4049/jimmunol.175.7.4236

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.