Mutation in the 5′UTR region of the HSP70-1 gene appears to influence the response to extracorporeal photochemotherapy

Extracorporeal photochemotherapy (ECP) is a therapeutic leukapheresis procedure which combines the effects of psoralens and UVA radiation and is used in the treatment of acute and chronic graft-versus-host disease (GvHD) following bone marrow transplantation, in acute rejection of some solid organ transplants (heart, kidney) and in some autoimmune diseases for patients resistant to conventional therapeutic protocols. The molecular mechanisms underlying this procedure are still not understood, but it is clear that they require activation of genes sensitive to UVA. Since it is known that UVA radiation induces an increase in intra- and extracellular synthesis of heat-shock-proteins 70 (HSP70), whose role as a cytokine has been recently discovered, we hypothesized that mutations in the HSP70 genes might influence the immunomodulatory effect of ECP thus explaining the well-recognized interindividual variability of response to ECP treatment. Twenty-nine patients (20 males, 9 females) were enrolled in this study. Nineteen had chronic GvHD following allogeneic bone marrow transplantation, 2 had diabetes mellitus, 4 pemphigus, 2 T-cell cutaneous lymphoma, 1 psoriasic arthritis and 1 patient was affected by dermatomyositis. The period of follow-up ranged from 6 months to 4 years. Each patient underwent a median of 18 photoapheretic procedures over a period of 6 months. We defined the polymorphism of the 5′ UTR region at position 190 of the HSP70-1 gene using a PCR-RFLP procedure. Twenty-one patients had a complete or good response and 8 had a partial response or remained stable. In the total sample the frequencies of HSP70-1 alleles were 56.9% for b1 and 43.1% for b2. According to the response to ECP we observed a significant increase of b2 frequency in those with poor response (75% vs 30.9% p=0.0025). The HSP70-1 b2/b2 genotype was present in 62.5% of the patients who showed a partial response or no change in their clinical condition, while it was present in 14.3% of the patients with a favourable evolution (complete or good response). This difference was statistically significant (p=0.027). Correlation is in progress between the HSP70-1 b1 and HSP70-1 b2 alleles and the level of HSP-70 mRNA expression and protein production.