No abstract

The regulation of major histocompatibility complex class II gene expression is directly involved in the control of normal and abnormal immune responses. In humans, HLA-DR, -DQ, and -DP class II heterodimers are encoded by a family of a-and fl-chain genes clustered in the major histocompatibility complex. Their expression is developmentally controlled and normally restricted to certain cell types. This control is mediated by cis-acting sequences in class II promoters and by trans-acting regulatory factors. Several nuclear proteins bind to class II promoter sequences. In a form of hereditary immunodeficiency characterized by a defect in a trans-acting regulatory factor controlling class II gene transcription, we have observed that one of these nuclear factors (RF-X) does not bind to its target sequence (the class H X box). A cDNA encoding RF-X was isolated by screening a phage expression library with an X-box binding-site probe. The recombinant protein has the binding specificity of RF-X, including a characteristic gradient of affinity for the X boxes of HLA-DR, -DP, and -DQ promoters. RF-X mRNA is present in the regulatory mutants, indicating a defect in the synthesis of a functional form of the RF-X protein.Class II major histocompatibility complex antigens are heterodimeric transmembrane glycoproteins. Their expression at the surface of antigen-presenting cells is essential for the recognition of foreign antigen by the T-cell receptor (1, 2). T-cell activation and antigen presentation depend not only on the structural specificity of the highly polymorphic class II molecules (1, 2), but also on the level of expression of class II antigens on individual cells (3). Regulation of expression of class II genes is therefore an important aspect of the control of the immune response.In humans, the genes encoding the a and f3 chains of the HLA-DP, HLA-DQ, and HLA-DR class II molecules are clustered in the D region of the major histocompatibility complex on chromosome 6 (4). These genes are subjected to tight and complex regulatory controls (4-7). Their expression is generally coordinated and restricted primarily to cells of the immune system such as B lymphocytes, activated T lymphocytes, macrophages, and dendritic cells. Within the B-cell lineage, class II expression is developmentally controlled. Finally, in certain class TI-negative cells, expression can be induced by stimulation with lymphokines such as interferon y or interleukin 4. Expression appears to be controlled primarily at the level of transcription.Progress has recently been made in the identification of cis-acting sequences in class II promoters (8-11) and of nuclear factors interacting with these sequences (8,(11)(12)(13)(14). We have identified five nuclear factors that bind to the promoter of the HLA-DR a-chain gene (ref. 14; M.K., W.R., C.H.S., and B.M., unpublished results). One ofthese factors, RF-X, binds to a sequence called the X box, which is present in all human and mouse class II promoters (15, 16). Interestingly, we have shown that RF-...

The X box of major histocompatibility complex class II promoters is essential for proper expression of class II genes. Here we show that two distinct protein-DNA complexes (A and B), which exhibit similar binding characteristics and identical contact points on the X box, can be formed. This suggests the existence of a family of related X box-binding factors. Complex B (and not complex A) is specifically affected in primary combined immunodeficiency, a congenital defect in class II gene regulation. RFX1, the first X box-binding protein cloned, encodes a functionally relevant factor present in complex A and not in complex B as originally suspected. This report also illustrates the need for caution in correlating specific cloned proteins with nuclear factors identified by DNA-binding assays, particularly when dealing with families of related proteins.

ADV is frequently seen in our pediatric SOT population. It presents in a variety of clinical presentation and can cause severe disease. In this population, there are very few studies to determine the safety of CDV as a potential therapeutic agent. We present the findings of our retrospective study evaluating the efficacy and safety of CDV as 2 separate dosing regimens. Regimen A uses the standard 5 mg/kg once a week (Regimen A), and the second uses the 1 mg/kg 3 times per week (Regimen B). Overall, the dosing regimen did not differ in nephrotoxicity, but Regimen B had a higher, although non-significant, rate of viral load clearance. This suggests that more frequent dosing at lower levels may be more efficacious without any significant side effects in our SOT population.