I have pasted a portion of a highly technical article. The take home message is that there is a tremendous amount of work being done on elucidating the underlying pathogenesis of various inflammatory skin disorders. Just as important is the fact that we now have the biotechnology to completely block the inflammatory cascade in a relatively safe fashion. If you actually get down to the bottom of the page and have not pulled out all of your hair, you will notice that they are in Phase II and Phase III trials involving certain “biological response modifiers”. While this one article focuses on psoriasis, contact dermatitis and atopic dermatitis, there is considerable overlap in the inflammatory skin response to that of rosacea sufferers – especially with regards to blocking inflammatory cytokines and neutrophils (two very hot topics in rosacea research right now). The progress made with these studies will directly impact the future treatment of rosacea. The cure for rosacea lies in the future use of biological modifiers that address the Kinase enzyme and possibly faulty vascular repair mechanisms.


Dr. Geoffrey Nase
Ph.D. Microvascular Physiologist

Experimental Dermatology
Volume 12 Issue 1 Page 1 - February 2003

Biological response modifiers and their potential use in the treatment of inflammatory skin diseases

Louise S. Villadsen 1 , Lone Skov 1 and Ole Baadsgaard 2

Abstract: In recent years, a more detailed understanding of the pathogenesis of several inflammatory skin diseases, combined with the developments within biotechnology, has made it possible to design more selective response modifiers. Biological response modifiers hold the potential for greater effectiveness and fewer side-effects than the current systemic therapies now used for severe psoriasis, contact dermatitis and atopic dermatitis. In the pathogenesis of inflammatory skin diseases, the immune system plays a pivotal role, and this is where biological response modifiers such as monoclonal antibodies, recombinant cytokines, or fusion proteins may be effective. Several biological response modifiers have already shown positive results in phase II/III clinical trials in skin diseases, and many new biological response modifiers are in progress.

Biological response modifiers relevant to inflammatory skin diseases can be divided into different groups

1. Monoclonal antibodies (mAbs) directed against surface molecules on inflammatory cells, cytokines or immunoglobulins (Ig): For instance anti-CD4, anti-CD11a, anti-E-selectin, anti-CD25, anti-TNF- , anti-IL-15 and anti-IgE.

a. The target for anti-CD4 is the cluster of differentiation 4 (CD4) molecules. CD4 is predominantly expressed on T cells and interacts with the major histocompatibility complex class II (MHC-II) on the antigen-presenting cell. This interaction is involved in T cell activation (6).

b. The target for anti-CD11a is CD11a, which is a subunit of leucocyte function associated antigen-1 (LFA-1), a T cell surface molecule. LFA-1 on the T cell interacts with intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, keratinocytes and antigen-presenting cells. This interaction is involved in T cell migration and T cell activation (7,8).

c. The target for anti-E-selectin is E-selectin, which is an adhesion molecule that mediates neutrophil, monocyte and eosinophil adhesion to activated vascular endothelium and skin-homing of memory T cells expressing cutaneous lymphocyte associated antigen (CLA) into lesional skin (9-11).

d. The target for anti-CD25 is CD25, the -subunit of the high-affinity IL-2 receptor. IL-2 is a major stimulus for T cell proliferation and differentiation and the high-affinity IL-2 receptor is expressed only on activated T cells (12).

e. The target for anti-TNF- is the proinflammatory cytokine TNF- (13).

f. The target for anti-IL-15 is the proinflammatory cytokine IL-15.

g. The target for anti-IgE is free IgE, which is central in the immediate hypersensitivity reaction (14,15).

2. Recombinant cytokines, e.g. recombinant IL-10 and IFN- , which down-regulate Th1 and Th2 cells, respectively (16-19).

3. Fusion proteins are typically a fusion of two parts. One part may for example direct specificity by binding the specific target, and the other part may be relevant to the stability of the protein. Both parts of the fusion protein may be crucial to the effect. The target-specific part of the fusion protein is important in selecting and eventually blocking the wanted target. The other part of the fusion protein may also be important to the effect, for instance by mediating toxicity if it is a toxin, or if it is an IgG molecule, by inducing antibody-dependent cell-mediated cytotoxicity as a result of the interaction of the IgG part of the fusion protein and the receptor Fc RIII (CD16) on natural killer cells. Examples of fusion proteins are: LFA3TIP, CTLA4Ig, DAB389IL-2, recombinant TNF- receptor and IL-15 mutant/Fc 2a.

a. LFA3TIP is a protein consisting of the first extracellular domain of human LFA-3 fused to the hinge CH2 and CH3 domains of human IgG1. LFA-3 is present on antigen-presenting cells and its ligand is CD2, which is found on T cells. CD2 is an important costimulatory molecule for T cell activation. The target for LFA3TIP is the interaction between CD2 and LFA-3 (20).

b. CTLA4Ig is a fusion of the extracellular domain of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and the Fc part of human IgG1. The target of CTLA4Ig is the interaction between CD28/CTLA4 on T cells and their common ligands, the costimulatory molecules, B7-1 (CD80) and B7-2 (CD86), on antigen-presenting cells (21).

c. DAB389IL-2 is a fusion of IL-2 and the diphtheria toxin. The target for the IL-2 diphtheria fusion toxin is the T cell subgroup expressing the high affinity IL-2 receptors (22,23).

d. The TNF- receptor fusion protein consists of soluble TNF- receptor and human IgG1 and its target is the proinflammatory cytokine TNF- (24).

e. IL-15 mutant/Fc 2a is a fusion of mutated human IL-15 and murine Fc 2a. The target of IL-15 mutant/Fc 2a is the interaction between the proinflammatory cytokine IL-15 and its receptor (25).