The colony-stimulating factors and collagen-induced arthritis: exacerbation of disease by M-CSF and G-CSF and requirement for endogenous M-CSF.

There is increasing evidence that the colony-stimulating factors (CSFs) may play a part in chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA). We examined the involvement of macrophage CSF (M-CSF or CSF-1) and granulocyte CSF (G-CSF) in collagen-induced arthritis (CIA), a murine model of RA. Daily injections of M-CSF or G-CSF, 20-24 days postprimary immunization with type II collagen, exacerbated disease symptoms in suboptimally immunized DBA/1 mice. Support for the involvement of endogenous M-CSF in CIA was obtained by studies in which neutralizing monoclonal antibody reduced the severity of established CIA and also by studies showing the resistance of M-CSF-deficient op/op mice to CIA induction. These studies show that M-CSF and G-CSF can be proinflammatory in CIA and provide evidence that macrophage- and granulocyte-lineage cells can exacerbate CIA. Our results also show that M-CSF-dependent cells are essential for CIA development, suggesting M-CSF may be a suitable target for therapeutic intervention in RA.

Increasing the supply of cadaveric kidneys for transplantation.

The number of cadaveric kidneys currently available for transplantation is insufficient. Therefore, the Center for Disease Control (CDC) undertook a collaborative project with the two transplant programs in Georgia to increase te retrieval of cadaveric kidneys. We used retrospective analysis to select productive hospitals, hospital-specific surveillance systems to identify potential donors, and procurement and retrieval evaluation to identify preventable deficiencies. During 900 hospital months of prospective surveillance, we identified a total of 555 potential donors by death record review, giving a potential donor rate of 2.3 donors/100 deaths (110 kidneys/million population/year). We observed an increase in the number of referrals, consent obtained from next of kin, and kidneys retrieved. This period of intensive activity demonstrated that additional kidneys can be retrieved by using systematic methods.

Protection from collagen-induced arthritis in granulocyte-macrophage colony-stimulating factor-deficient mice.

The involvement of granulocyte-macrophage CSF (GM-CSF) in collagen-induced arthritis (CIA) was examined using GM-CSF-deficient mice. Although CIA is generally considered to be restricted to mice of the H-2q or H-2r haplotypes, we examined the role of GM-CSF in the CIA model using GM-CSF-deficient (-/-) and wild-type (+/+) mice on a C57BL/6 (H-2b) background. Mice were immunized by intradermal injection at the base of the tail with chick type II collagen followed by a repeat injection 21 days later. We found, based on both clinical and histologic assessments, that wild-type mice on this background developed severe CIA, while the GM-CSF-deficient mice had virtually no disease. Mice that were heterozygous for the GM-CSF gene (+/-) collectively displayed an intermediate response between those of the GM-CSF(+/+) and GM-CSF(-/-) groups, suggesting a gene dosage effect. GM-CSF(+/+) and GM-CSF(+/-) mice exhibited CIA responses ranging from mild (single digits) to severe swelling of all four paws, while in the few GM-CSF(-/-) mice that developed CIA the disease was confined to single digits. Despite the putative role of GM-CSF in dendritic cell development, GM-CSF-deficient mice exhibited both humoral and cellular (delayed-type hypersensitivity) responses to type II collagen; however, the cellular response was significantly reduced in the GM-CSF-deficient mice compared with the wild-type controls. These findings suggest that GM-CSF is required for CIA development in mice and support the idea that GM-CSF is a key cytokine in inflammatory joint disease.

Blockade of collagen-induced arthritis post-onset by antibody to granulocyte-macrophage colony-stimulating factor (GM-CSF): requirement for GM-CSF in the effector phase of disease.

There is mounting evidence for a role of the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) in inflammatory disease, including arthritis. In the present study, we examined the effectiveness of treatment of collagen-induced arthritis (CIA) with a neutralizing mAb to GM-CSF. DBA/1 mice were immunized for the development of CIA and treated at different times, and with different doses, with neutralizing mAb to GM-CSF or isotype control mAb. Anti-GM-CSF mAb treatment prior to the onset of arthritis, at the time of antigen challenge, was effective at ameliorating the ensuing disease. Modulation of arthritis was seen predominantly as a reduction in overall disease severity, both in terms of the number of limbs affected per mouse and the clinical score of affected limbs. Importantly, anti-GM-CSF mAb treatment ameliorated existing disease, seen both as a reduction in the number of initially affected limbs progressing and lower numbers of additional limbs becoming affected. By histology, both inflammation and cartilage destruction were reduced in anti-GM-CSF-treated mice, and the levels of tumor necrosis factor-a and IL-1beta were also reduced in joint tissue washouts of these mice. Neither humoral nor cellular immunity to type II collagen, however, was affected by anti-GM-CSF mAb treatment. These results suggest that the major effect of GM-CSF in CIA is on mediating the effector phase of the inflammatory reaction to type II collagen. The results also highlight the essential role of GM-CSF in the ongoing development of inflammation and arthritis in CIA, with possible therapeutic implications for rheumatoid arthritis.