Gamma Interferon Induced Organ Regeneration

The salamander is the only vertebrate that has a substantial capacity to regenerate severed limbs and damaged organs. A necessary condition for this response is the lack of scar formation (fibrosis) at the site of injury. I postulate that suprapharmacologic doses of gamma interferon administered locally to the site of traumatic injury or disease induced organ capacity loss might unlock regenerative capabilities in humans. Preliminary data involving a case of advanced pulmonary fibrosis (scarring) is presented wherein suprapharmacologic doses of inhaled gamma interferon induced the regeneration of functional lung parenchyma. Moreover, I postulate that potent inhibition of fibrosis in the adult human may allow the activation of embryonic development programs at the site of organ or tissue injury. INTRODUCTION Injury in the adult human is typically followed by the healing response which includes the laying down of a disordered collagen matrix [1-4]. This scar or fibrotic response has been postulated to be one of the impediments to regeneration of the damaged organ [1-4]. The adult salamander is the most well studied model of vertebrate organ and tissue regeneration in the adult [1-4]. An adult salamander can grow exact replacements for severed limbs and other lost body parts. The early stages of tissue injury in the salamander and the adult human are similar. However, while a scar forms in humans at the site of tissue or organ injury, scarring does not occur in the salamander. Instead, the salamander reactivates an embryonic development program to repair or replace the large body part (tissue or organ) [1-4]. Gamma interferon has been postulated to be a useful inhibitor of fibrosis [5]. However, to date gamma interferon has not shown activity in human fibrotic disease. In fact, in one study where gamma interferon was administered subcutaneously, it failed in a trial of pulmonary fibrosis [6]. I postulate this failure was due to the lack of local suprapharmacologic dosing of gamma interferon. THE HYPOTHESIS Local delivery of suprapharmacologic doses of gamma interferon to the site of injury to a human organ or tissue prevents scarring (fibrosis) allowing tissue or organ regeneration in the adult. Additionally, long-term delivery of suprapharmacologic doses of gamma interferon may unlock embryonic tissue regeneration programs even after substantial scar formation (fibrosis) has occurred. EVALUATION OF THE HYPOTHESIS Fibrosis inhibition is a necessary condition for limb and organ regeneration in the adult [1-4]. Suprapharmacologic doses of gamma interferon were effective in an end-stage patient with pulmonary fibrosis (severe scarring of the lung parenchyma) (see preliminary data). Traumatic injury or injury due to disease or therapeutic interventions can result in loss of organ capacity, loss of function of limbs and unsightly scars. By administering high dose gamma interferon (on the order of 20 million units per day or more) to the site of trauma or disease, fibrosis may be suppressed to a degree that allows regeneration of the organ or tissue. Delivery of gamma interferon can be intermittent or continuous via inhalation, injection, implantable polymers or pumps. This approach is readily testable in animal models and humans. PRELIMINARY DATA – REPORT OF A CASE Pulmonary fibrosis (lung scarring) is thought to be caused by many factors ranging from toxic insults to the lung as is seen with chemotherapeutic agents such as bleomycin, as well as radiation therapy for breast, lung, lymphoma and other cancers. Inhalation of toxic or cell mediated immunity triggering allergens can also cause a fibrotic response to lung injury. An autoimmune disease targeting primarily lung tissue or an autoimmune disease associated with other autoimmune diseases, such as systemic scleroderma or rheumatoid arthritis with associated lung involvement is the basis of many cases of interstitial pulmonary fibrosis [1]. The usual interstitial pneumonitis variant (UIP) of interstitial pulmonary fibrosis probably represents the end stages of a more acute form of the disease [7]. The UIP form is characterized histologically by replacement of lung parenchyma by substantial amounts of collagen (scar tissue) in the interstitium and a chronic mononuclear cell inflammatory infiltrate with a relative absence of eosinophils [7,8]. Typically the fibrotic process impairs lung elasticity, reduces total lung capacity (TLC) reduces forced vital capacity (FVC), reduces the forced expiratory volume in one second (FEV1), reduces alveolar volume (Va) and substantially impairs gas exchange (Dsbadj). The gold standard for diagnosis is an open lung biopsy. High resolution CT scan typically shows “ground glass” changes which can provide a high degree of certainty in making the diagnosis [5-13]. Many of these patients, including the patient described in this report, complain of a gradual increase in a dry cough over months or years and a progressive increase in dyspnea on exertion over the same time period [7]. The prognosis of interstitial fibrosis of all causes is poor, with life expectancy of 2-6 years [7,9] and the average life expectancy at the time of diagnosis being 2.8 years [513]. Patients with advanced disease (i.e., carbon monoxide diffusing capacity, Dsbadj, loss of 60% or greater and substantial loss of forced vital capacity and lung volume) and advanced age (over 65) have a much worse prognosis [7,9]. Overall, less than 10% of patients with all types of interstitial lung fibrosis respond to standard therapy of systemic corticosteroids and immunosuppressants and/or chemotherapeutic agents such as cyclophosphamide or azathioprine or other immunosuppressive regimes [7]. Additionally, these treatments substantially increase the risk of pulmonary infection, which can be rapidly fatal in patients with limited pulmonary reserve. None of these treatments has been shown in well-designed clinical trials to substantially restore lost lung function or to prolong life and it is questionable whether they have a favorable impact on morbidity or life expectancy. Recently, gamma interferon-1b, given subcutaneously at what the medical community currently considers high daily doses (200 micrograms per day, 4 million International Units per day) three days per week has not shown any substantial activity in the advanced phase of this disease [6]. Gamma interferon has been shown to increase host defense against bacteria, mycobacteria and other pulmonary pathogens including Staphylococcus aureus, Listeria, mycobacterium tuberculosis, mycobacterium leprae, atypical mycobacteria and Pneumocystis carinii. The mechanism of action may be its ability to increase superoxide production and nitric oxide production by immune cells, induction of 2° cytokines and increased antibody dependant cellular toxicity (ADCC) [10]. No therapy has been shown in a well-designed clinical trial to prolong life in any form of interstitial pulmonary fibrosis. In fact, therapeutic options are so poor, that many clinicians recommend only supportive care, particularly for elderly patients, due to the poor risk benefit ratio of current treatment [7]. If patients with interstitial pulmonary fibrosis are young enough and otherwise healthy, they many be considered for lung transplantation [11]. However, this procedure is very costly, there are not enough lungs to satisfy the need, and the survival benefit is moderate to poor. There is a great need for safe, highly effective and well-tolerated treatments for pulmonary fibrosis of all causes and subtypes. The direct infusion of an immune enhancer into the lungs of individuals suffering from interstitial pneumonitis in general, and autoimmune interstitial pneumonitis in particular, brings with it the risk of worsening the lung damage from increased inflammation, worsened autoimmunity, cellular damage by inflammatory cells and their products, as well as increased fibrosis as is seen with tumor necrosis factor alpha (TNF-α) [12]. Additionally, a capillary leak syndrome or acute respiratory distress syndrome (ARDS) is a possibility as is seen with TNF-α and interleukin-2 [13,14], even when these cytokines are administered systemically. Additionally, many cytokines induce secondary cytokines or chemokines which can cause further toxicity, especially locally. One would expect a priori, that inhalation of high doses of gamma interferon might accelerate the pathological changes of interstitial pulmonary fibrosis both directly and indirectly through induction of 2° cytokines, or chemokines, induction of an ARDS response [13,14], direct damage to lung parenchyma through the release of highly reactive and damaging superoxide and nitric oxide species and a variety of other mechanisms. I report a case of advanced UIP, which was put into complete remission, with near complete restoration of his lost lung function, which can only be explained by regeneration of new lung parenchyma. This response occurred in less than fourteen months with very little morbidity or toxicity with a novel two-agent regime, which included aerosolized, nebulized gamma interferon-1b starting at low doses and escalating to suprapharmacologic doses, and high dose intravenous immunoglobulin, which was added to control gamma interferon side effects.