I n t r o d u c t i o n
Primary im m unodeficiency diseases are characterised by a susceptibility to recurrent and often fatal opportunistic infections as well as other im m unological problems such as autoimmune diseases. Many types o f primary im m unodeficiency diseases have now been identified with a wide spectrum o f clincial manifestations and underlying genetic causes.
Severe com bine im m unodeficiency (SCID) is a rare fatal syndrome characterised by profound deficiencies o f T- and B -cell function (Bortin and Rimm, 1977; Fischer, 1 99 2). Since the initial report o f a patient with SCID over 50 years ago the genetic origins o f the disease have been demonstrated to be highly variable (Fischer, 1992; Giblett et a i , 1972; G riscelli et a i , 1978; Noguchi et al., 1993; Fuel et a i , 1998; Russell et a i , 1995; Schwarz et al., 1996; White et al., 2000). Nevertheless, the clinical course o f the disease is consistent, with susceptibility to infection leading to death in infancy being the inevitable outcom e o f the disease. However, significant advances have been made in treatment options for SCID patients over the past 30 years with HCT proving an extrem ely successful therapy (Buckley et a i , 1999; Fischer et al., 1990). In addition, gene therapy offers a more recent alternative to HCT for the correction o f the genetic defect leading to SCID (Fischer et a i , 2000).
However, with regard to HCT, this treatment option has numerous associated problem s. G VH D and infections (as a result o f delayed immune reconstitution) remain significant barriers to the success o f this therapy. In addition, a number o f SCID patients remain deficient in T -cell function in the long term and (with only a few exceptions) none o f the transplanted SCID patients restore normal B -cell function, remaining dependent on infusions o f im m unoglobulins throughout life.
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Clearly, the absence o f T-cells in SCID patients before HCT gives us a unique opportunity to study the developm ent o f T-cells in the absence o f a com peting immune system. The previous results from chapter 4 demonstrated that some aspects o f pre-transplant conditioning could affect thymic output. However the SCID patients reported previously (Buckley et al., 1999) did not receive any pre-transplant conditioning and therefore allowed the study o f thym ic-dependent reconstitution in the absence o f pre-transplant conditioning or a com peting immune system. However, SCID patients have very small thymuses that weigh less than 1 gm and lack thym ocytes and correct thymic architecture. This has prompted speculation that the SCID thymus would be unable to support T -cell maturation after HCT (Buckley et al., 1997; Neuhaus and Briner, 1986; N ezelof, 1992). A recent study by Patel et al. alleviated these concerns somewhat by demonstrating that the SCID thymus was able to support T-cell maturation in patients after HCT (Patel et al., 2000). However, thymic output was not sustained over the course o f the study and declined to undetectable levels by 17 years post-HCT. This observation, along with the lack o f B -cell function noted in patients after HCT has raised further concerns over engraftment o f the most primitive self renewing stem cells.
Therefore, the first aim o f this chapter was to assess thym ic-dependent reconstitution (using TREC analysis) in two groups o f SCID patients who were between 1 and 17 years post-HCT. These groups were divided into patients that received pre-transplant conditioning and those who did not. Where possible, T -cell phenotyping was also carried out.
Another primary im m unodeficiency disease that offers a unique opportunity to study thymic function and T-cell development is the DiG eorge syndrome. The D iG eorge syndrome is a rare congenital disorder in which the thymus, parathyroids and heart all fail to develop properly. In com plete DiGeorge syndrome, patients have severely reduced or absent T -cell function (Markert et a i , 1999). However, the severity o f the syndrome varies a great deal. Similar to SCID, the genetic causes o f DiG eorge syndrome are not fully understood although a deletion within chrom osom e 2 2 q l 1.2 is most frequently observed (de la Chapelle et al., 1981; Driscoll et al., 1993).
Several therapies have been used to treat the im m unodeficiency associated with D iG eorge syndrome. HCT has been attempted but has been limited in its (Borzy et al., 1989; Bowers et al., 1998; G oldsobel et al., 1987; Markert et al., 1998). Thymus transplantation has also been considered as a treatment option (August et al., 1968; Daga et a i , 1984; Markert et al., 1997; Pahwa et a i , 1979) but these attempts have also been largely unsuccessful (Borzy et al., 1979; Dictor et al., 1984; R eece et al., 1981). A recent study by Markert et al. analysed DiG eorge syndrome patients who received thymic tissue transplants. This study was able to demonstrate that grafted thymic tissue was able to
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reconstitute the T-cell compartment and that survival o f the patients was extended for a considerable period of time (Markert et al., 1999).
Therefore, the second aim o f this chapter was to evaluate thymic function in a number o f DiG eorge syndrome patients (defined on the basis o f having the 2 2 q ll.2 deletion) as part o f their clinical evaluation.
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