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Biological Modifiers of
Inflammatory Diseases

W. Winn Chatham

During recent decades, the elucidation of specific inflammatory differentiation and proliferation may therefore provide novel
mediators and identification of lymphocyte lineages that con- interventions for managing a variety of inflammatory disorders
tribute to the pathology underlying chronic inflammatory associated with autoimmunity, including SLE. 2
disorders have identified immunological targets amenable to
modification by use of recombinant DNA technologies. The KEY CONCEPTS
resulting biological modifiers of inflammatory diseases have
revolutionized the treatment of rheumatoid arthritis (RA), Interferons: Therapeutic Potential
inflammatory bowel disease (IBD), psoriasis, spondyloarthropa- • Interferon-α (IFN-α) has been used with success to enhance resolution
thies, antineutrophil cytoplasmic antibody (ANCA)–associated of chronic viruses, notably hepatitis C virus (HCV); newer antivirals
vasculitis syndromes, systemic lupus erythematosus (SLE), and are supplanting the need for IFN therapy in HCV.
other autoimmune diseases, as well as allergic disorders. These • IFN-β has immunomodulatory effects that are of benefit in the treatment
targeted therapies, although costly, offer individuals affected by of certain subsets of patients with multiple sclerosis (MS).
these disorders options for better disease control and less of the • Type 1 IFNs (including IFN-α and IFN-β) may unmask or trigger flares
morbidity associated with greater exposure to broader immune of autoimmune disease, most notably systemic lupus erythematosus
(SLE).
suppression and/or corticosteroid use. This chapter summarizes • IFN-γ may be of some benefit in the management of patients with
the biological modifiers of inflammatory diseases that are currently chronic granulomatous disease (CGD) not responding to antifungal
available or in development classed by mechanism of activity and antibacterial prophylactic regimens.
and molecular nature.

IMMUNOMODULATORY CYTOKINES Interferons
IFNs, released primarily by T lymphocytes as well as dendritic
Recombinant Interleukin-2 (Aldesleukin) cells (DCs) in the context of stimulation of Toll-like receptors
First identified as a T-cell growth factor, recombinant interleukin-2 (TLRs) have a wide array of immunomodulatory effects that
(rIL-2) has potent immunomodulatory and antitumor activity, include upregulation of genes governing angiogenesis, cell dif-
promoting the proliferation, differentiation, and recruitment of ferentiation, expression of human leukocyte antigen (HLA)
T cells, B cells, and natural killer (NK) cells (Table 89.1). rIL-2 molecules, and production of inflammatory cytokines. IFN-α
has primarily been used therapeutically in patients with advanced and IFN-β bind to the same cell surface receptor (IFN-1R) and
melanoma and in patients with advanced renal cell carcinoma. are designated type-1 IFNs, whereas IFN-γ binds to a different
IL-2 is a potent inducer of proinflammatory T-cell cytokines, receptor (IFN-2R) and is designated as a type 2 IFN. Recombinant
such as IL-1, tumor necrosis factor-α (TNF-α), and interferon-γ preparations of all three IFNs have been used for the management
(IFN-γ), all of which likely play a major role in dose-related IL-2 of inflammatory disorders associated with chronic viral infection,
toxicity, which may include hypotension, cardiac arrhythmias, primary immunodeficiency (PID), or select autoimmune disorders
increased capillary permeability with pulmonary edema, fever, (most notably multiple sclerosis [MS]). Although there are
and rarely death. The use of aldesleukin in patients with cancer immunomodulatory attributes that render IFNs useful in certain
has been increasingly supplanted by more targeted immune- circumstances, constitutional symptoms and upregulation of a
enhancing “checkpoint” therapies targeting T-cell death receptors wide variety of genes that promote inflammation frequently
(programmed death 1 [PD-1]) and cytotoxic T lymphocyte limit the use of both type 1 and type 2 IFNs.
antigen-4 (CTLA-4), which have comparable antitumor effects
with much less acute toxicity. Interferon-α
More recently, the administration of low-dose rIL-2 has been Recombinant IFN-α2b (rIFN-α2b) has most commonly been
shown to promote preferential growth and proliferation of used in combination with ribavirin for treatment of hepatitis
regulatory T cells (Tregs) without significantly affecting the release C, including hepatitis C virus (HCV)–associated cryoglobulin
3
1
of inflammatory mediators by CD4 T cells. Such low-dose syndromes. Other disorders linked to viral infections, including
regimens of rIL-2 have been used with success in suppressing lymphomatoid granulomatosis (caused by Epstein-Barr virus
manifestations of graft-versus-host disease (GvHD) and may [EBV]) and polyarteritis nodosa (caused by hepatitis B virus
1
also favorably impact the course of type 1 diabetes. The use of [HBV]), have been successfully treated with regimens incorporat-
4
rIL-2 and/or other cytokine therapies promoting enhanced Treg ing IFN-α2b as part of the treatment regimen. Refractory retinal
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