Latest Research - an Overview

Dr Patricia Martinez, Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, Western Australia
From a paper presented to the AGM of the Lupus Group of WA, 8 October 2002
 

Understanding an autoimmume disease as the basis for lupus related research

• The normal immune system is comprised of T- and B-cells that discriminate between self and non-self molecules.
• When the immune system becomes dysfunctional these cells lose their ability to discriminate and thus the self-molecules are treated as foreign, leading to immunological reactions, including the production of antibodies ( ie. autoantibodies ) which attack healthy cells and tissues eg. as in SLE
• B-cells have a major role in initiating and maintaining underlying immunopathological mechanisms of SLE, such as
  1. producing autoantibodies
  2. presenting molecules to other cells of the immune system and
  3. disrupting the ability of T-cells to recognise self-molecules as such.
• When auto(antibodies) bind the molecules they are directed against, an "immune complex" is formed. Immune complexes can then be deposited in tissues and lead to tissue damage.

Current approaches in treating SLE are associated with :

• Non-specific effects suppressing many components of the immune system. This can lead to increased vulnerability to serious infections
• Potentially severe adverse effects - diabetes, osteoporosis, hypertension, cataracts and sterility - especially when high doses are needed, and
• A lack of effective non-toxic therapy.

Research pathway 1 - clinical research studies
Research pathways to be profiled include :

1. Use of Oestrogen in SLE
   • Generally medical practitioners will avoid prescribing oral contraceptives ( OC's - an exogenous hormone ) to women with SLE as it is thought that these have the potential to increase activity of SLE. This has been based on the belief that there is a hormonal link with SLE due to the greater incidence of SLE in women and evidence of abnormalities of oestrogen metabolism. Animal studies in mice with lupus have shown lupus flares with oestrogen.
   • However current research studies have suggested no significant increase in the rate of flares in patients on OC's. Current studies to confirm this include :
     • A large (multicentre, randomised, double blinded placebo-controlled) trial to test the effect of exogenous female hormones on disease activity and severity in women with SLE
     • A study ( randomised ) of OC or HRT in women with SLE to determine :
       • effect of OC's that have low-dose synthetic oetrogens and progestins on disease activity in premenospusal women with SLE, and
       • effect of HRT with oestrogens and progestins on disease activity in postmenopausal women.
2. Use of complement ( C3a ) levels as a predictor of SLE flares
   • The complement system is a cascade of reactions that occur as part of inflammation. This system is implicated in organ damage that occurs in SLE and therefore is an ideal target for therapeutic intervention
   • In a SLE flare, the complement system is activated, resulting in :
     • Decreased levels of some components of the cascade - C3 and C4, and
     • Increased complement breakdown products - i.e. C3a, C5a, and C5b9. These contribute to some manifestations of SLE by stimulating inflammation
3. Therapeutic interruption of the complement cascade
   Therapy pathways being considered include the :
   • production of monoclonal antibodies to C5, which attach to this molecule and inhibit this part of the complement system being activated, resulting in a block of complement split products. Studies in lupus-prone mice have shown that such an approach has resulted in inhibition of renal disease
   • removal of immune complexes and other components of the complement cascade, resulting in improvement in clinical manifestations.
4. Search for genes associated with lupus
   • Research into the genes responsible for the development of SLE has focused on :
     • nalysis of families in which many members have SLE
     • the genetic analysis of mouse models - including the functional analysis of some genes that contribute to SLE and the identification of genes that suppress SLE
   • C4 genes produce one of the components of the complement cascade - the C4 protein, and are thought to play a major role in the risk of developing SLE.
   • C4 genes may vary in the presence or absence of a sequence known as HERV-K (C4), whose function (if any) is not known ÿ Research undertaken to date by Dr Martinez has been analysing this HERV-K(C4) sequence. It is the intention to study SLE patients in WA by analysing the occurrence of this sequence in SLE patients and assessing its relationship to disease manifestations and laboratory findings.

Research pathways 2 - novel therapeutics
The interest in developing 'novel therapeutics' for SLE comes from the need for safer and more effective drugs. The difficulty in such development is that the pathogenesis of SLE is not well understood and a target/s for such therapy would need to be chosen - the inhibition of T ­and/or B -cell function vs. use of autoantibodies vs. use of soluble mediators of inflammation. Several potential therapeutics under research will now be considered:

1. Selective B-cell Modulation - LJP 394
   Anti-ds(double stranded)DNA antibodies show a potential pathogenic role in renal disease in SLE. LJP 394 is a selective B-cell immuno-modulator that has been developed and shown in studies of mice to reduce these anti-dsDNA antibodies ( both serum and in the spleen ) and therefore improve renal function, improving survival rates. In human trials there appears also to be a benefit in renal function, however further studies are needed to confirm this.
2. Anti-CD20, Anti-CD22
   CD40 and CD40L are lymphocyte cell surface molecules that participate in the immune response. CD40 is expressed on B-cells and CD40L is expressed ( transiently ) on activated T-cells. It is known that these two molecules play an integral role in antibody ( protective proteins ) synthesis. When these molecules were blocked by Anti- CD40 antibody in both mice and humans it was found that they demonstrated favourable safety and decreased renal disease. Further studies are underway. CD22 is a molecule that is expressed exclusively on the surface of B-cells. An antibody developed - known as hLL2 - binds to this CD22 and is found to be safe, tolerable, effective, and have the ability to deplete B-cells causing damage.
3. Use of genetically engineered molecules
   SLE has overactive B-cells in circulation and in most tissues. New molecules being engineered are focusing on treatments that, for example, will prevent the production of Antinuclear Antibodies (ANA's) that cause so much damage. T-cells surface molecules ­ CD28 and gp39 ­ determine how cells distinguish between normal molecules and foreign material. Molecules have been genetically engineered that block the function of CD28 and gp39 and have been shown to inhibit disease in mice with SLE. So far, it appears that for effectiveness, long term therapy is required, but the sustained benefit over time is apparent.
4. Immunosuppression
   Current immunosuppressant agents and cytotoxic drugs modulate T and B-cell activity, but they are associated with side effects, including increased susceptibility to infection. New agents are being developed that may have fewer side effects, be more selective in their target for treatment and be able to prevent autoantibody production. It is important to remember the following in relation to autoantibodies :
   • In healthy people : B-cells that are capable of producing these autoantibodies usually self-destruct without causing any harm
   • In people with SLE : autoantibody production may arise due to the persistence of the B-cells that produce the autoantibodies, environmental activation of otherwise normal B-cells to produce autoantibodies, or stimulation of B-cells capable of producing autoantibodies by T-cells.
5. Bone marrow transplantation (BMT)
   This type of research is in the early stages of clinical investigation, but may be of benefit in people in whom conventional therapy for SLE has failed. The goal of such therapy is to eliminate disease-causing B and T-cells from the body, and reconstitute the bone marrow with cells that are free of disease and that function normally. Two types to be considered include :
   • Autologous BMT - these are undifferentiated marrow stem cells that are presumed free of disease and obtained from peripheral blood after using growth factors. The bone marrow and peripheral lymphoid cells are then ablated and the bone marrow then reconstituted by reinfusion of the patients stored stem cells and conditioned with growth factors.
   • Allogeneic BMT ­ this is technically more difficult and hazardous. Stem cells must be obtained from a normal HLA-matched donor, the actual patient must have their bone marrow and peripheral lymphoid cells ablated, and then the donor stem cells are transfused to patient to reconstitute the patient's bone marrow. This is however the favoured technique as the immune abnormalities associated with SLE also affect stem cells and thus in this method the patient has new (donor) stem cells.
6. Dehydroepiandrosterone : DHEA
   DHEA is an important intermediate in the sex steroid pathway and is converted to potent androgenic steroids. In SLE there is a preponderance of females, suggesting that oestrogen may contribute to disease activity and androgens may reduce disease activity. Studies have demonstrated beneficial effects from daily use of DHEA on lupus disease activity, with some side effects however of acne and hirsutism. GL701 is an investigational new drug that enhances DHEA levels. It has been suggested that lupus flares and other symptoms may be due to a deficiency of DHEA; thus the development of GL701. Further studies are being undertaken to assess safety and efficacy.

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