Working with the Transgenic Animal Model Core to Explore Paclitaxel-Induced Peripheral Neuropathy and the Role of Complement

With the help of the Biomedical Research Core Facilities Transgenic Animal Model Core (TAMC), Feng Lin, Ph.D. (Cleveland Clinic Lerner Research Institute) and colleagues may have elucidated the role of complement in the development of chemotherapy-induced peripheral neuropathy (CIPN).

CIPN is a common side effect of cancer chemotherapy, which can lead to poor quality of life and impact the progression of treatment. The exact mechanism is not yet known, but evidence suggests the immune system and inflammation may play a role. CIPN is often seen with the chemotherapeutic drug, paclitaxel, which is understood to cause neuronal damage through inducing structural and functional changes upon binding to the microtubule within the axon.

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According to Lin et al., there is evidence that complement is involved in other forms of neuropathic pain. Complement is a key component of the innate immune system which, through a series of cleavages involving the central protein, component 3 (C3), is involved in formation of the membrane attack complex (MAC) that causes lysis and death of infected cells. With the potential for connection, the authors decided to investigate further.

Using CRIPSR/Cas9 technology, TAMC staff provided Lin et al. with a C3 gene knockout rat. Rat was the preferred model, as its complement system more closely represents the human version, when compared to mouse. Through several experiments, the authors found an attenuated response—both in cell injury and complement activation—in C3 KO rats administered paclitaxel when compared to wild-type (WT). While they acknowledge that further research is necessary, their findings could have important clinical implications for the treatment of patients experiencing CIPN.

These findings were recently published in the Journal of Immunology. Find the publication here.

Xu J1,2, Zhang L1, Xie M1, Li Y1, Huang P1, Saunders TL3, Fox DA4,5, Rosenquist R2, Lin F1. Role of Complement in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy. J Immunol. 2018; 200(12):4094-4101.

1Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195; 2Department of Pain Management, Anesthesiology Institute, Cleveland Clinic, Cleveland, OH 44195; 3Transgenic Animal Model Core Facility, University of Michigan, Ann Arbor, MI 48109; 4 Division of Rheumatology, University of Michigan, Ann Arbor, MI 48109; 5 Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI 48109