Richard,
I did a preliminary search of articles published by Immunex on IL1 alpha and beta between 1985-1995.
Results, articles of significance:
Citation:
C Jacobs, Young D, Tyler S, Callis G, Gillis S, Conlon PJ, In vivo treatment with IL-1 reduces
the severity and duration of antigen-induced arthritis in rats., J Immunol 141: 9, 2967-74, Nov 1,
1988.
Abstract
IL-1 has been implicated in the pathogenesis of arthritis. Although IL-1 injected in vivo into normal joints results in a
transient inflammatory reaction, we have shown that three weekly repetitive injections of IL-1 do not produce a
progressive inflammatory condition suggestive of chronic arthritis. In fact, priming normal joints with three weekly
IL-1 intraarticular injections results in a significant reduction in joint swelling and diminished histopathologic
alterations/lesions caused by subsequent methylated BSA-induced arthritis. Similarly, post treatment with IL-1
intraarticular injection after arthritis induction reduced arthritic swelling and joint injury if IL-1 was given during the
developing stage of arthritis. Our results suggest that IL-1 might limit arthritic inflammation and progressive cartilage
destruction through an, as yet, undetermined mechanism(s). Further in vivo investigations are required to determine
the therapeutic utility of IL-1 in reducing early arthritic inflammation.
Citation:
PJ Morrissey, Charrier K, Alpert A, Bressler L, In vivo administration of IL-1 induces thymic
hypoplasia and increased levels of serum corticosterone., J Immunol 141: 5, 1456-63, Sep 1,
1988.
Abstract
Administration of IL-1 alpha or IL-1 beta to normal mice induces a decrease in thymic cellularity, the magnitude of
which depends on the number of injections and dose of IL-1. Twice daily injections of 200 ng of IL-1 alpha or -beta
for 4 days results in a 90% decrease in thymic cellularity, which regenerated after cessation of treatment. Study of
thymocyte subpopulations revealed that the number of CD4+/CD8+ thymocytes was dramatically decreased in
IL-1-treated mice. Functional assessment of the CD4-/CD8- population from treated animals showed that these cells
had adequate mitogenic responses in vitro and that the proportion of these cells in cycle was not different from control
CD4-/CD8- cells. IL-1 treatment also prevented the regeneration of thymic cellularity after irradiation. The use of
strains of mice differing genetically at the Ly 1 locus to construct radiation bone marrow chimeras demonstrated that
bone marrow-derived thymocyte precursors were able to seed the thymus in the IL-1-treated animals. Again,
however, the CD4+/CD8+ thymocyte population was significantly decreased. Thymic repopulation occurred upon
cessation of IL-1 therapy. Finally, we determined that a single i.p. injection of IL-1 caused a three-fold increase in
serum corticosterone levels, which peaked approximately 3 h after IL-1 administration. Thus, an IL-1-dependent
increase in serum corticosterone levels may be responsible for the observed thymic hypoplasia.
Citation:
DE Williams, Morrissey PJ, Alterations in megakaryocyte and platelet compartments following in
vivo IL-1 beta administration to normal mice., J Immunol 142: 12, 4361-5, Jun 15, 1989.
Abstract
IL-1 has been shown to stimulate the release of granulocyte-macrophage CSF, granulocyte-CSF, and
macrophage-CSF from "accessory cell populations" in vitro, and it stimulates the appearance of colony-stimulating
activity in the sera of mice in vivo. This cytokine has also been proposed to act on primitive hematopoietic progenitor
cells to stimulate expression of receptors for the CSF. We sought to determine whether IL-1 beta could influence
platelet and/or megakaryocytes and their progenitor cells following in vivo administration to normal mice. Our results
demonstrated that, although administration of IL-1 beta clearly expands the pool of megakaryocyte-CFU and
acetylcholinesterase-positive megakaryocytic cells (primarily in the spleen), it causes a transient and dose-dependent
reduction of circulating platelets. The associated thrombocytopenia can be abolished by splenectomy before IL-1 beta
administration, and is not temporally associated with the development of splenomegaly.
Medline ID:
95081628
Citation:
JG Giri, Wells J, Dower SK, McCall CE, Guzman RN, Slack J, Bird TA,
Shanebeck K, Grabstein KH, Sims JE, et al, Elevated levels of shed type II IL-1
receptor in sepsis. Potential role for type II receptor in regulation of IL-1 responses.,
J Immunol 153: 12, 5802-9, Dec 15, 1994.
Address:
Immunex Research and Development Corporation
Seattle
WA 98101.
Abstract
Two types of cellular IL-1Rs have been characterized and cloned from both human and murine sources. The type II
IL-1R has a very short cytoplasmic domain and does not seem to participate in IL-1 signaling. We demonstrate that
type II IL-1Rs are released from the surface of neutrophils in response to treatment with TNF or endotoxin. In
addition, serum from patients with sepsis syndrome contains elevated levels of soluble type II IL-1Rs. Neutrophils
isolated from patients with sepsis have greatly enhanced expression of type II IL-1R mRNA and cell surface receptors
and are therefore a likely source for the shed receptors in serum. Of the three forms of IL-1, soluble type II IL-1R
binds IL-1 beta with highest affinity and also selectively inhibits IL-1 beta activity. We propose that increased cell
surface expression and rapid release of preformed type II IL-1R from neutrophils, as a soluble IL-1 beta binding
protein, represents a mechanism that has evolved for regulating IL-1 activity in sepsis.
Medline ID:
94267227
Citation:
PJ Morrissey, Charrier K, Treatment of mice with IL-1 before infection increases
resistance to a lethal challenge with Salmonella typhimurium. The effect correlates
with the resistance allele at the Ity locus., J Immunol 153: 1, 212-9, Jul 1, 1994.
Address:
Immunex Corporation
Seattle
WA 98101.
Abstract
Administration of a single dose of IL-1 alpha to various strains of mice approximately 16 h before a lethal infection
with Salmonella typhimurium resulted in a significant augmentation of survival in most Ityr, but in no Itys strains of
mice. Lower numbers of bacteria were observed in the liver and spleen in response to IL-1 pretreatment shortly after
infection in all Ityr strains of mice tested, including the congenic C.D2-Ityr mice. Treatment with IL-1 alpha after
infection had no effect on survival in either Ityr or Itys mice. A combination of IL-1 alpha pretreatment with IL-1
alpha post-treatment did not increase survival over the effect of IL-1 alpha pretreatment alone in Ityr mice and did not
increase the survival of the Itys mice. The combination of IL-1 alpha pretreatment with GM-CSF post-treatment was
effective in Ityr but not in Itys strains of mice. Thus, IL-1 alpha pretreatment enhances the resistance of Ityr, but not
Itys strains of mice to a lethal challenge with S. typhimurium by up-regulating antibacterial mechanisms shortly after
infection.
I believe the information indicates IL-1 needs alot of work to become fully valued. It appears to me that IMNX all but abandoned work on IL1 after the late 1980's or early 1990's in favor of work on the IL-1 receptor. As I indicated earlier, Imnx has a Ph I clinical trial of IL-l receptor ongoing.
I would now like to hear from CIST as to how they will now proceed. Additionally, they may have information which would be of value in assessing the future development of IL1 related products.
I'd appreciate comments/further analysis.
Best,
Greg |
