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Potential Hope for CFIDS/ME Patients with ICL

by Alan Cocchetto, NCF Medical Director  2005

Over a decade ago, Dr. Paul Cheney, Dr. Anthony Komaroff and other CFIDS/ME physicians had identified a condition known as ICL in some of their patients.  ICL is the acronym for "Idiopathic CD4 Lymphocytopenia" and it denotes a dramatic loss of a specific T-cell lymphocyte known as a CD4 (T-helper) cell.  The extensive reduction in CD4 cells is a hallmark characteristic of AIDS, a disease characterized by a progressive loss of function of the immune system.

   Scientists at Enzon Pharmaceuticals have been studying the mechanisms involved in CD4 depletion and have developed a potential drug treatment for CD4 T-cell lymphopenia. Since ICL is typically defined as a CD4 cell count below 200 cells/microliter, a condition that unfortunately is present in some CFIDS/ME patients, this treatment may offer a means to restore some of the immune dysfunction that has occurred as a result of the disease process.  More importantly, it may provide a way to reduce opportunistic infections that often accompany this illness since CD4 cells are critical to appropriate immunologic response.

   The NCF believes that scientific evidence points to CFIDS/ME as a result of a chronic infection.  As such, the immune system is chronically activated due to this "unknown" infection.  As a
consequence, this cellular activation must therefore play a vital role in the pathology of this disease.  Abnormal levels of RNaseL, cellular apoptosis, etc. have been reported in CFIDS/ME and this bolsters our beliefs here.  Thus, a chronic infection certainly has the potential to cause cellular depletion, as is seen in ICL, via T-cell apoptosis.  Scientists have discovered that some patients with ICL have a deficiency in an important enzyme known as adenosine deaminase.

   A deficiency of adenosine deaminase (ADA) results in severe combined immunodeficiency (SCID) in humans.  ADA is an enzyme in the purine degradation pathway that deaminates adenosine and deoxyadenosine to yield inosine and deoxyinosine respectively.  The enzyme has a wide tissue distribution with the highest activity occurring in lymphocytes. ADA deficiency inhibits the normal catabolism of purines and results in the accumulation of metabolic substrates that are especially toxic to lymphocytes.  ADA deficiency results in T-cell apoptosis (cell death) as well as an alteration to T-cell differentiation and therefore an alteration in the production of mature T-cells.

   The good news is that a suggested drug treatment for ADA deficiency is Adagen. Adagen (intramuscular injection) is a modified enzyme used for enzyme replacement therapy for the treatment of SCID associated with ADA deficiency.  Adagen provides specific and direct replacement of the deficient enzyme.  Adagen administration can eliminate the toxic metabolites of ADA deficiency and result in improved immune function.  However, it is imperative that treatment with Adagen be carefully monitored by measurement of the level of ADA activity in plasma.  Monitoring of the level of deoxyadenosine triphosphate (dATP) in erythrocytes is also helpful in determining that the dose of Adagen is adequate.

   The NCF is confident that PWC/ME patients that suffer from ICL will be encouraged by this information.
1.  p53 expression is required for thymocyte apoptosis induced by adenosine deaminase deficiency; Benveniste P, Cohen A; Proc Natl Acad Sci 1995, Aug 29;92(18):8373-7

2.  Adenosine deaminase and thymocyte maturation; Doherty PJ, Pan S, Mulloy JC, Thompson E, Thorner P, Barankiewiecz J, Roifman CM, Cohen A; Scand J Immunol 1991, Apr; 33(4):405-10

3.  Mechanisms of apoptosis in developing thymocytes as revealed by adenosine deaminase-deficient fetal thymic organ cultures; Thompson LF, Vaughn JG, Laurent AB, Blackburn MR, Van De Wiele CJ; Biochem Pharmacol 2003, Oct 15;66(8):1595-9

4.  Fundamental Immunology; Raven Press; William Paul - editor

5.  Osler's Web: Inside the labyrinth of the Chronic Fatigue Syndrome Epidemic; Hillary Johnson; Crown Publishers, 1996

6.  Adagen injection PDR drug information;

7.  Method of treating CD4+ T cell lymphopenia in immuno-compromised patients; US Patent #5,728,560 issued March 17, 1998 to Inventors: Shorr RGL, Clark MA, Goddard DH; Assignee: Enzon, Inc.

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