The Role of IL-10 Overexpression on the Properties of Healing Tendon
Tendon healing in adults following injury is often complicated by scar
formation that is related to the inflammation that occurs following tendon
injury. Interestingly though, it has been found that fetal wound healing
occurs at a faster rate and in the absence of scar formation. One of the
critical factors in scarless fetal wound repair is interleukin-10. Interleukin-10
(IL-10), originally termed cytokine inhibitory factor, is a 35-kDa-homodimeric
product of Th2 cells, B cells and macrophages. It is a potent anti-inflammatory
cytokine that has been implicated in preventing an immune response to the
fetus and its "foreign" antigens.
With the knowledge that certain factors, such as the lack of IL-10, can
affect tendon healing, gene therapy is an emerging technology that holds
great promise in modulating tendon healing and, as a result, improved clinical
results. Local delivery of growth factors or cytokines can potentially be
used as a method of improving healing, reducing adhesions or both. The majority
of studies that have investigated the inferior properties of healed tendons
and ligaments have mainly focused on the effect of applying exogenous cytokines
to injured tissue, via gene therapy. These studies have confirmed that injured
ligaments and tendons treated with cytokines have improved properties when
compared with untreated injured controls. As a result, cytokines play a
vital role post-injury, and as a result, have the ability to affect post-traumatic
scarring in tendon and ultimately tendon function and the properties of
tendon healing.
Interestingly, while it is well known that healing of adult tendon occurs via scar formation, there is extensive experimental evidence that early and midgestational fetal tissue responds to injury in a fundamentally different way than adult tissue. Fetal wound healing occurs in the absence of scar formation that has been attributed to the absence of a substantial inflammatory response. This healing response has been seen in a multitude of fetal tissues, including skin, articular cartilage, nerve, bone and tendon. Furthermore, modulation of this scarless fetal wound repair has elucidated key factors that may play a role in the prevention of scar formation. One of these factors is the presence of interleukin-10, which, as stated previously, is a potent anti-inflammatory cytokine. Fetal skin healing in transgenic IL-10 knockout mice occurs with scar formation, while wild type fetal skin heals without scar formation. This finding supports the concept that the presence or absence of IL-10 can modulate scar formation. It is findings such as this that have opened up the avenue of gene therapy as a potential to alter tendon healing and as a result, scar formation.
Gene therapy has focused on using viruses, such as adenovirus, to deliver
selected genes to the target of interest. It has been shown in adult skin
that adenoviral-mediated over-expression of IL-10 creates a permissive environment
for scarless wound healing. Equine infectious anemia virus (EIAV) is a retrovirus
within the subfamily lentiviridae, which includes the primate lentivirus,
human immunodeficiency virus (HIV-1 and HIV-2) and simian immunodeficiency
virus (SIV). This project is testing the hypothesis that overexpression
of IL-10 via a lentiviral vector will lead to reduced level of inflammation
post-injury that will lead to better collagen organization during the processes
of proliferation and remodeling. It is thought that this better collagen
organization will lead to a stronger biomechanical construct following tendon
injury.