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Published on: November 7, 2017
Cyclin-dependent kinase inhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus
Carla Zoja1, Federica Casiraghi, Sara Conti
1Mario Negri Institute for Pharmacological Research, Bergamo, Italy. zoja@marionegri.it
Objective:
To examine whether the cyclin-dependent kinase (CDK) inhibitor seliciclib ameliorates autoimmune nephritis in (NZB x NZW)F(1) mice.
Methods:
In experiment 1, NZB x NZW mice received seliciclib (100 mg/kg or 200 mg/kg) or vehicle by gavage, beginning at age 2 months and ending at 8 months of age. In experiment 2, seliciclib (200 mg/kg) was administered alone or combined with low-dose methylprednisolone, starting at age 5 months, when immune complex deposition in the kidney had already occurred. Animals were followed up until all vehicle-treated mice died. In 2 additional groups of NZB x NZW mice treated with seliciclib or vehicle from 2 months of age until 5 months of age, splenocytes were isolated and tested ex vivo for T cell and B cell activity.
Results:
Seliciclib, given at an early phase of disease, prolonged survival, delayed the onset of proteinuria and renal function impairment, and protected the kidney against glomerular hypercellularity, tubulointerstitial damage, and inflammation. Combining seliciclib with low-dose methylprednisolone in mice with established disease extended the lifespan and limited proteinuria and renal damage more than treatment with either agent alone. Seliciclib limited immunologic signs of disease, reducing glomerular IgG and C3 deposits and levels of serum anti-DNA antibodies. Moreover, it inhibited ex vivo T cell and B cell proliferative responses to polyclonal stimuli. T cell production of interferon-gamma and interleukin-10 and B cell release of IgG2a were reduced by treatment with seliciclib.
Conclusion:
These findings suggest that CDK activity may be a useful target in the treatment of systemic lupus erythematosus. A direct immunomodulatory action of seliciclib on T cells and B cells may be one of the mechanisms underlying the beneficial effects.
Insights
The cyclin-dependent kinase (CDK) inhibitor seliciclib showed therapeutic potential for autoimmune nephritis in mice. Seliciclib demonstrated immunomodulatory effects, improving survival and reducing kidney damage in a lupus nephritis model.
Area of Science:
- Immunology
- Pharmacology
- Nephrology
Background:
- Autoimmune nephritis, a severe kidney inflammation, poses a significant health challenge.
- Systemic lupus erythematosus (SLE) often involves autoimmune nephritis, necessitating novel therapeutic targets.
- Cyclin-dependent kinases (CDKs) play a role in immune cell function and proliferation.
Purpose of the Study:
- To investigate the efficacy of seliciclib, a CDK inhibitor, in ameliorating autoimmune nephritis in (NZB x NZW)F(1) mice.
- To evaluate the immunomodulatory effects of seliciclib on T cells and B cells in a lupus nephritis model.
Main Methods:
- Mice were treated with seliciclib at different doses and stages of disease, alone or in combination with methylprednisolone.
- Splenocytes were isolated and tested ex vivo for T cell and B cell activity.
- Renal pathology, proteinuria, survival, and serological markers were assessed.
Main Results:
- Early-phase seliciclib treatment prolonged survival, delayed disease onset, and protected kidneys from damage.
- Combination therapy in established disease extended lifespan and reduced renal damage more than monotherapy.
- Seliciclib reduced immune complex deposition, anti-DNA antibodies, and inhibited T and B cell proliferation ex vivo.
Conclusions:
- CDK activity represents a promising therapeutic target for systemic lupus erythematosus.
- Seliciclib exhibits direct immunomodulatory effects on T and B cells, contributing to its beneficial outcomes in autoimmune nephritis.
