advances-in-protein-chemistry

21 increases the functional effects of NKT, NK and CD8+ T cells and may be effective in treating human cancers in combination with
other first line therapies.
Autoimmune Diseases
Autoimmune disease is an immune malfunction in which immune response is directed against self molecules. They arise when the
immune system responds aggressively to the individual’s own tissues through recognition of self-antigens. Such an immune reaction
which evokes pathological consequences could be due to involvement of humoral, cell mediated or complement mediated immunity.
It is believed that autoimmune diseases affect 5-6 percent of the entire population. Among the most common autoimmune diseases are
rheumatoid arthritis, multiple sclerosis, type-1 diabetes, pernicious anemia and Graves diseases which accounts for about 90 percent of
all cases. In general, women are three times more likely than men to develop autoimmune diseases [27,28].
Lymphocytes specific for self-antigens are found in all individuals whether they are healthy or suffering from an autoimmune
condition. The immune system maintains such broad responsive lymphocyte repertoire to provide protection against infections and
cancers. However within this repertoire contains autoreactive cells but these cells are tightly suppressed and regulated by the immune
system. Autoimmune diseases results from breakdown of such regulation or tolerance. Although there are varieties of mechanisms for
induction of autoimmunity [20], the exact mechanism or causes remains to be worked out. The ideal treatment of autoimmune diseases
would be induction of long lasting antigen specific tolerance. Achieving this mission is hindered by the fact that efforts to identify the
specific provoking autoantigen in large number of auto-diseases are still underway. Moreover, induction of such a specific tolerance is
difficult during ongoing immune response.
Therapeutic approaches
The current strategies for treating autoimmune diseases are aimed at providing management program that reduces pain and
discomfort, prevents deformities and loss of bodily function so that patient leads a near normal life. The treatment strategies
include treatment with therapeutic peptides (discussed below (Figure 7)), treatment with immunomodulatory and cytotoxic agents
(azathioprine, cyclosporine, cyclophosphamide), non steroidal anti-inflammatoryagents (ibuprofen, aspirin, paproxen), corticosteroid
(prednisone, methylprenisolone), disease modifying anti-rheumatic drugs (methotrexate, hydroxycholoroquine, sulfasalazine). These
immunomodulatory and cytotoxic agents along with other drugs are either anti-inflammatory or immunosuppressive and are already
widely used for autoimmune as well as other diseases though with some (sometimes life threatening ) side effects.
Figure 7: Protein/Peptide based therapy of autoimmune diseases.
There are number of therapeutic approaches that have been used to treat or manage autoimmunity in experimental animal models
and human clinical studies [20]. These therapies usually involve proteins such as antibodies, peptides such as cytokines that target
either the culprit causative agents (eg cells) or eliminated cytokines that induce pro inflammatory reactions. Soluble peptides such as
glatiramer [29] serve as tolerogen when delivered inside the host body. Such peptides tend to induce “tolerance” in the host which results
in depression in auto immune reactions. Use of some important proteins and peptides in managing autoimmune diseases are discussed below.
Targeting cytokines: New and novel non-antigen specific therapeutic approaches target cytokines. As mentioned previously,
cytokines are protein mediators of inter-cellular communication and are involved in a wide variety of biological activities including
immune responses. Role of different cytokines in autoimmune diseases have been well studied and it has become clear that excessive
production of pro-inflammatory cytokines as well as lack of anti-inflammatory ones constitutes to pathogenesis of several autoimmune
diseases. Fine tuning the cytokine balance may have therapeutic value and can be achieved by neutralization of pro-inflammatory
cytokines or administering or inducing anti-inflammatory ones.
There are three major pro-inflammatory cytokines – Tumor necrosis factor α (TNF-α), interleukin-1 (IL-1) and IL-6. These cytokines
can be neutralized in a variety of different ways such as production of soluble cytokine receptor, monoclonal antibodies against cytokines
or production of non-activating cytokine receptor antagonists [30]. Clinical trial with chimerized monoclonal antibodies against TNF
(infliximab) in human have given encouraging results in rheumatoid arthritis (RA), Crohn disease (CD),psoriasis and psoriatic arthritis
[31]. Infliximab (trade name -remicade) is a chimeric monoclonal antibody against TNF that has antigen binding site of mouse origin
and remaining antibody derived from human IgG1 antibody. After infliximab administration, clinical results were encouraging even
when RA patients were resistant to multiple DMARDs (disease modifying anti-rheumatic drugs). Patient having steroid-resistant active
CD also showed clinical and endoscopic improvement by single infusion of infliximab.
Similar results were reported for fully human anti-TNF antibody –Adalimuab (humira) that was found to be effective in RA, CD,
and psoriatic arthritis.
IL-1, another proinflammatory cytokine have been implicated in the pathogenesis of autoimmune diseases such as RA [31].
Neutralizing of IL-1 have been achieved by IL-1 receptor antagonist which blocks the binding of both IL-1α and IL-1β to IL-1 receptor.
Anakira, a human recombinant IL-1 receptor antagonist is approved for the treatment of RA. Blocking of other inflammatory cytokines
such as IL-6, IL-15 have also proven successful strategy in ameliorating RA. Neutralizating IL-6, a cytokine that upregulates secretion of
acute phase proteins by humanized monoclonal, anti IL-6 receptor antibody in rheumatoid arthritis are currently in progress.
Systemic administration of recombinant cytokines to patients of autoimmune diseases have also been explored with some success
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