IL-1 and TNF-a: Fascinating past and present

IL-1 and TNF-a: Looking to the past for answers

I recently wrote a review of the discovery of IL-1 and TNF-a for the Rheumatology Report Volume 2, Number 1 (Fall 2007). I took excerpts from this review for this blog and expanded on those I felt were most interesting to share.

For hundred of years, physicians and scientists have endeavored to discover why fever occurs and regresses in human disease. The discovery of cytokines and their inhibitors has led to a more complex understanding of the regulation and dysregulation of the immune system. The history of the discovery TNF-a and the biologic TNF-a inhibitors will be addressed as well as IL-1b and its inhibitor IL-1Ra. A review of the role of the IL-1b and TNF-a in synovial inflammation and potential targets for treatment of Rheumatoid Arthritis including gene based therapy, vaccine therapy and mesenchymal stem cell therapy will be outlined.

Coley’s toxin and the discovery of TNF-a

IN 1891, Dr. William Coley frustrated by the inability of aggressive surgery to result in a cure of sarcoma searched through the medical records of his hospital. Dr. Coley found the records of a 7 year old child who recovered from sarcoma following an infection with erysipelas. Dr Coley then proceeded to treat a patient with lymphoma with multiple injections of streptococcal cultures at 3-4 day intervals. The tumor underwent necrosis after the patient developed an attack of erysipelas and the patient remained disease free for 8 years. Throughout the remainder of his career, Dr. Coley used injection of streptococci and heat killed streptococci plus Serratia marcescens, (“Coley’s toxin”) to treat patients with malignant tumors. The dose of “Coley’s toxin” needed to produce a temperature of 40-40.5 degrees Celsius in order to induce necrosis of the tumor. Coley observed that infection resulted in a systemic response that resulted in tumor destruction.1 Many years later in 1975, an endotoxin-induced serum factor was found to be responsible for the necrosis of tumors and named Tumor Necrosis Factor. 2

Inhibition of TNF

In 1988, an inhibitory protein of TNF was isolated from the urine of febrile patients. 3 The protein inhibited with the function of TNF by blocking the binding of TNF to its’ receptor. The protein was found to bind both TNF-a and TNF-b. 4 In subsequent years, many members of the TNF-family members and their receptors were discovered as well their roles in rheumatic disease and novel ways to block their activity were developed. 5 In 1993, chimeric monoclonal antibodies to TNF-a were used to block its activity and to successfully treat rheumatoid arthritis. 6 Modification of a TNF receptor for the successful treatment of rheumatoid arthritis was accomplished in 1997 with the design of a recombinant soluble TNF receptor (p75) linked to the Fc portion of human IgG1. 7 The soluble TNF receptor (p75) binds and blocks the activity of both TNF-a and TNF-b.

The History of IL-1 and its Inhibition

In 1926, Zinsser and Tamiya discovered that contact with tissues of animals infected with tuberculosis resulted in the production of a toxic factor in uninfected cells. They suspected that a protein constituent of mycobacterial growth or of the mycobacterium itself stimulated cells to liberate a toxic substance on other cells or within the cell itself. 8 These observations may have been the first described effects of IL-1.

In the 1970s, numerous investigators simultaneously identified factors that modulate lymphocyte function including lymphocyte-activating factor, mitogenic protein, helper peak-1, t cell-replacing factor III, T cell-replacing factorMF, B cell-activating factor and B cell differentiation factor. It was determined that these factors were identical and in 1979 all were renamed IL-1. 9 The pleiotropic actions of IL-1 explain its simultaneously description and discovery by multiple investigators. In subsequent years, different receptors and inhibitors of IL-1 were discovered, importantly IL-1 Receptor Antagonist (IL-1Ra) at the University of Colorado. The first clinical observation of variations of IL-1Ra was in children with systemic juvenile inflammatory arthritis and reported in 1987. 10 In 1996, the use of recombinant human IL-1Ra, anakinra, was used to treat patients with rheumatoid arthritis. 11 More recently, IL-1Ra has been successfully used in treating patients with juvenile onset and adult onset Still’s disease. 12-14

How the synovium may be subject to inflammation in rheumatoid arthritis

The initial site of inflammation in rheumatoid arthritis has remained elusive. Ochi et al reported on the ability of fibroblastic stromal cells from the bone marrow to migrate to the joint space and form synovial tissue in the mouse model of collagen-induced arthritis. This specific population of fibroblast stromal cells can act as nurse-like cells and have the ability to interact with lymphocytes and monocytes and induce cellular differentiation and promote biological activities that mimic features of rheumatoid inflammation. 15 The findings of this study provide evidence of the bone marrow’s ability to maintain a disease state and to direct localization to the joints. It has yet to be established how the nurse-like cells of fibroblast stromal origin migrate from the bone marrow to the joint space.

A mechanism by which antibodies may gain access to joint compartment was reported by Binstadt et al, 2006. Using intravital imaging, they identified that arthritogenic antibodies from the K/BxN arthritis model caused vasopermeability localized to sites leading to the development of arthritis in normal mice. This vasopermeability was dependent upon mast cells, neutrophils and FcgRIII but not complement, TNF or IL-1. 16 Neither of these studies identified the initial site of inflammation or trigger of inflammation in rheumatoid arthritis, but provided insight into the mechanisms of continued disease activity and identify potential targets for future treatment modalities.

Cadherin- 11, an adhesion molecule, was shown to play a critical role in establishing synovial cell- to cell- contact necessary for synovial lining formation. Caherin-11 is necessary for the establishment of the K/BxN serum mediated transfer of arthritis as cadherin-11-null mice failed to develop inflammatory arthritis and had a poorly organized synovium. Similarly, use of anti-cadherin 11 in established arthritis helped to ameliorate disease in the K/BxN serum transfer mouse model of arthritis.17

IL-1b and TNF-a induce the overgrowth of synovial cells

In collagen-induced arthritis, IL-1b and to a lesser extent TNF-a were found to induce the expression of synoviolin in mouse synovial fibroblasts. IL-1b induced synoviolin transcription, which in turn enhanced IL-1b induced synovial fibroblast proliferation. The synovial fibroblasts produced more IL-1b for the induction of synoviolin leading to a positive feedback loop that may be critical in maintenance of rheumatoid inflammation. 18

Targeting inflammatory cytokines through gene based therapy

In a phase-I trial, fibroblast-like synoviocytes were transduced with a retroviral vector containing the gene for IL-1Ra and injected into the metacarpophalangeal joints. The transfer and expression of IL-1Ra was safely and successfully accomplished but no follow-up clinical studies are planned using this method. 19

A phase I dose escalation trial using delivery of a recombinant adeno-associated virus containing the TNF-receptor-Fc immunoglobulin fusion gene (tgAAC94) has been conducted and a phase I/II trial was being conducted when a study participant died.19 The woman had a low-grade fever and fatigue for several days before she received a second dose of active drug, dosed at10 trillion tgAAC94 particles per milliliter. Within a few days after the second injection, her condition worsened and she died of histoplasmosis. Last month, at the American College of Rheumatology meeting in Boston, results of an investigation into the woman’s death were released. Genetic analyses of tissue samples from the woman showed 500,000 copies/microgram of tgAAC94 in the injected knee, but fewer than 30 copies/microgram in other tissues including the other knee, liver, spleen, tonsil, and bowel. Wild-type AAV copies were found at low or undetectable levels in the various tissues. The investigation found no evidence that the agent had been contaminated with Histoplasma. 20 The FDA announced this week that the trial has been re-opened for enrollment.

Before gene therapy is successful, it needs to be determined if neutralizing antibodies to the viral vectors will render the therapy ineffective. Additionally, methods for producing vectors needs to be optimized and how therapeutic gene expression will be regulated in the human host needs to be established. 19 Methods to measure the suppression of systemic TNF activity attributable to gene therapy need to be designed to determine the activity of the gene therapy. Moreover, there are numerous safety concerns to be addressed.

TNF-a kinoid vaccination as a potential therapy for rheumatoid arthritis

Le Buanec et al, 2006 have developed a vaccine using a keyhole limpet hemocyanin-hTNF-a immunogen. When injected into hTNF-a transgenic mice in incomplete Freund’s adjuvant, a high-titer of neutralizing antibodies to hTNF-a were produced that eliminated the bioactivity of hTNF-a and resulted in reversal of arthritis. 21 Further studies are needed in other mouse models and caution should be used in the interpretation of these results, as completely limiting the function of TNF-a in humans would likely result in deleterious effects including increased risk of infection and malignancy.

Immunomodulation through the use of mesenchymal stromal cells

The report of an interdisciplinary meeting addressing the potential role for multipotent mesenchymal stromal cells in the pathogenesis and management of autoimmune diseases was published in January 2007. Mesenchymal stromal cells, derived from the bone marrow, in vitro exhibit antiproliferative effects on T and B lymphocytes, dendritic cells, natural killer cells and B cell tumor cell lines. 22,23 In the collagen-induced arthritis mouse model, injecting a murine mesenchymal cell line systemically or intra-articularly was not effective in modulating disease and labeled mesenchymal stromal cells were not found in the articular injection sites. The lack of therapeutic effect was attributed to increased levels of TNF-a and its reversal of the immunosuppressive properties of the mesenchymal stromal cells. 24 More data is needed on the optimal source of mesenchymal stromal cells as those from autoimmune diseased patients may not be equivalent to those from healthy individuals.25 Additionally, optimal timing, location and number of cells to be given have yet to be determined. 23

Final Thoughts

The extensive scientific and clinical work over the last century has led to exciting discoveries in immune system biology and the pathogenesis of autoimmune diseases. The experiences of the past with infectious agents and the responses they elicit led to the discovery of cytokines and there potential use in altering immune response to benefit individuals. Although blocking of one cytokine with current biologic therapies has led to improved management of rheumatoid arthritis, for many patients blocking only one cytokine may not be sufficient. 26 New ways of targeting cytokines and their regulation may be possible in the future with gene therapy, immunization therapies and tissue specific synovial based therapies.
We shall not cease from exploration
And the end of all our exploring
Will be to arrive where we started
And know the place for the first time.

Little Gidding V, Four Quartets, T.S. Eliot (1943)

For an interesting discussion of Dr. Coley’s work and progress made after his death see: http://www.coleytoxins.com/1893htm.

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