Re: NEW p58: CHS suppressed in mice by previously irradiated psor...

From: Alexander Potapenko
Date: 12/13/97
Time: 10:32:23 AM
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The suppression of delayed type reactions (contact and delayed type hypersensitivity) is very important in PUVA-therapy and photopheresis. The question is what is the molecular basis of this effect? When we treat human skin or blood (irradiate them in the presence of sensitizer) all possible photoreactions of psoralens occur: type I - free radical; type II - singlet oxygen; type III - oxygen independent photoaddition to DNA and unsaturated fatty acids; finally reactions proceeding with participation of products of psoralen photooxidation (let us designate them as type IV) also take place. How to answer the question which of them is significant? The most direct evidence in favor of some of them is to perform the treatment in such a way that only one of these reactions will occur while the others will be completely excluded. It is very difficult to imagine the procedure in which we can remain for example type III reactions and exclude all the others. The same difficulty we shall meet in the case of type I and type II reactions. The only easy experiment in this direction is to perform the treatment by the way when only type IV reactions will take place, while types I, II and III will be completely excluded. It is really very easy: you need to preirradiate psoralen in the absence of substrate and than in the dark to add photoproducts to substrate; in such a way reactions of types I, II and III will be completely excluded because they proceed only when substrate is irradiated in the presence of sensitizer. Thus our experiments with preirradiated psoralen show that type IV reactions play very important role in immunosuppression and by all probability in therapy. Currently clinical trials (double blind control) are in progress and we see very promising effect of POP-therapy in case of eczema. It is difficult presently to compare effectiveness of POP-therapy and PUVA-therapy, the experimental data are absent. But principal opportunity of creation of POP therapy is clear, perhaps it will be very long way before such therapy will be really created. Surely POP therapy is better in that respect that skin photoaging will be excluded. Risk of cancer (not necessarily skin cancer, the other types of cancer may be significant) may be the same as in PUVA-therapy due to immunosuppression? Preirradiated psoralen is very complicated mixture of photoproducts (see C18 report on this conference). Biologically active POP products are very labile (they are destroyed by Fe ions, ascornate, reduced glutathione, and by other reducing agents) and it is very difficult task to get them purified to investigate chemical structure. What can we see now? Kinetic considerations show that POP products responsible for hemolysis of erythrocytes and for immunosuppression are different [Ā. Ā. Kyagova, N. N. Zhuravel, M. M. Malakhov, E. P. Lysenko, W. Adam, C. R. Saha-Möller, A. Ya. Potapenko. Supression of delayed-type hypersensitivity and hemolysis induced by previously photooxidized psoralen: effect of fluence rate and psoralen concentration. Photochem. Photobiol., 65, # 4, 694-700, 1997.]. Kinetic schema is the following: 1) Psoralen + light -> labile intermediate A; 2) A -> immunosuppresing final product (POP1); 3) A + A -> hemolysin (as the result of recombination of two molecules of product A giving product POP2). Thus at high fluence rate of light (or high concentration of psoralen) will be produced mainly POP2 (hemolysin) while at low fluence rate (or low concentration of psoralen) will be produced mainly POP1 products (immunosuppression). What is very interesting the same kinetic schema is proposed by Moor et al in the report devoted to the effects of fluence rate in the case photodynamic therapy. PDT is more efficient at low fluence rate like POP therapy! Perhaps the mechanisms are relatively close. Our recent data indicate that POP practically do not influence on humoral immune response [A.A.Kyagova, E.V.Nagurskaya, V.A.Bekhalo, I.Yu.Chernyakhovskaya, I.V.Belichenko, A.Ya.Potapenko. The attenuation of effectors and induction of suppressors of delayed type hypersensitivity reaction under the treatment with psoralen photooxidation products. Russian J. Immunol. 1996, 1, #1, 61-68.]. Apoptosis induced by POP was not investigated. I have no any idea about the effects of preirradiated sunscreens, it may be interesting. Alexander Potapenko.

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