CD45 is the prototypical transmembrane PTP, and is highly expressed in all hematopoietic lineages (Sasaki et al. 2001). It is well established that CD45 is critical for T and B cell activation, primarily via activation of the Src kinase Lck (Thomas 1999). Under resting conditions, Lck is maintained in an inactive state via intramolecular interactions between its C-terminal phosphory-lated tyrosine (Y505) and its SH2 domain. During TCR engagement, CD45 dephosphorylates Y505 on Lck, thus allowing for activation of kinase activity. Activated Lck then phosphorylates its substrates to transmit the TCR signals that ultimately lead to transcription of genes that are important for T cell function, such as interleukin-2.

Mice lacking CD45 demonstrate impaired T cell differentiation and activation as well as B cell activation and are therefore severely immunodefi-cient (Kishihara et al. 1993; Byth et al. 1996). Two recent descriptions of clinically relevant CD45 mutations associated with severe combined immunodeficiency disease (SCID) in humans correlate well with the phenotype reported for the CD45-deficient mice (Kung et al. 2000; Tchilian et al. 2001). In those cases, mutations of CD45 confirm that this PTP serves as a modifier gene in immunodeficiency.

As a therapeutic target, anti-CD45 antibodies have demonstrated an an-tileukemic effect when used either unconjugated or attached to radioactive iodine (Nemecek and Matthews 2002). For example, 131I-labeled anti-CD45 antibodies have been used to deliver radiation directly to leukemic cells, because CD45 is found on cell surface isolated from most of leukemia patient samples (Countouriotis et al. 2002). Clinical trials of this antibody-based therapy using anti-CD45 antibodies are currently in phase I/II (

CD45 is also presumed to be a good immunomodulatory molecule to promote transplantation tolerance based on its accessibility as a transmem-

brane protein (Fecteau et al. 2001; Ko et al. 2002; Pagel et al. 2002). Allograft rejection is a T cell-dependent process, and interference with T cell activation through T cell receptor (TCR) can induce anergy in CD4+ T cell clones. Indeed, in this context, allograft rejection has been shown to be suppressed using an antibody against CD45RB isoforms (Lazarovits et al. 1996). One possible mechanism by which such an interaction induces allograft tolerance involves the upregulation of CTLA4 (cytolytic T lymphocyte-associated antigen 4) which is an important T cell down-regulatory molecule (Fecteau et al. 2001).

Very recently, it has been shown that 77 C/G mutation in the human CD45 gene, which results in increasing CD45RA isoform expression on cell surface, is linked to several autoimmune diseases such as systemic sclerosis and hepatitis (Vogel et al. 2003), suggesting CD45 inhibitors and/or antibodies are potent therapeutics for those autoimmune diseases.

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