Our study showed a clear reversal in CD4/CD8 ratio after exposure to radiation, compared with the control group, and this was agreed with several studies, which indicated that irradiation can destroy the immune system to a specific degree through a lack of peripheral lymphocyte count, including CD4 and CD8. [11].
However, these studies differed in the evaluation of radiation sensitivity and were as follows:
1- Some studies did not indicate any difference, in CD4:CD8 ratio as a result of radiation exposure [12].
2- Other studies indicated a clear decrease in CD8 count, and thus a clear increase in CD4:CD8 rate.[13]
Where CD4 is more resistant to radiation at 2-Gray dose than CD8, but CD8’s return to normal levels is faster than CD4’s [14]. This theory proved to be striking, and after a time of exposure to nuclear bomb radiation, there was a clear variability in the cell count, with a normal CD4 cell count and a decrease in CD8 cell count in the exposed organisms [15] Plus, with the exception of only one report, the CD4 cell count increased in people exposed to radiation in the Chernobyl tragedy [15].
3- However, other studies have suggested that CD4 is more sensitive than CD8, and there was a decrease in CD4:CD8 ratio [16]. This was agreed with our research (Table 1) where a clear reversal in CD4/CD8 ratio within the normal-radiated control group (NORMAL+ X) was observed (P<0.001) compared to the normal control group.
The reason for the decrease in CD4 cells is that CD4 lymphocytes show elevated levels of apoptosis in response to radiation, associated with high levels of Ser46 phosphorylation on the protein p53 ,which cause apoptosis [17].
After that , the cells recover from radiation, where previous studies have shown that Granulocyte colony-stimulating factor (G-CSF) promotes hematological blood healing, where it enhances the differentiation and reproduction of myeloid progenitor cells [18]. As G-CSF is activated, stem cells migrate to the thymus and may induce their reproduction and differentiation within the thymus [18].
The thymus is the primary site of T-cell development, but this organ is very sensitive to radiation. Radio damage is transient, and regeneration is rapid and clear, so CD8/CD4 returns to normal levels within 14 days. And G-CSF synergizes with cytokines like IL-1 , IL-3 ,IL-6, develop the thymus cells [18].
However, our research did not indicate a recovery in CD4:CD8 frequency, which may be due to bone marrow injury as well as thymus injury, because many researches have indicated that the action and size of the thymus decreases within 6 months when animals exposed to radiation at a dose of 2-5 Gray [19]. It is worth noting that the re-synthesis depends not only on the proliferation of precursors resistant to radiation within the thymus, but also from the mobilization of stem cells from the bone marrow to the thymus, where they differentiate to become mature T cells [18].
Our study showed the ability of Bry+ ZFN and antivirals to treat radiation damage and return CD4/CD8 to normal levels. Several studies have indicated the ability of bryostatin to protect living organs from irradiation in irradiation-exposed mice. The mechanism by which protein kinase activators enhance radiation protection is that the activation of accessory cells by bryostatin causes the release of growth factors, such as G-CSF, IL-1 and IL-6 which have a clear role in radiation protection. Bryostatin may modify the action of GM-CSF Granulocyte-macrophage colony-stimulating factor [20].
Activating of Pk-C signals by bryostatin may also contribute to the expression of certain oncogenes, such as c-jun tumor genes, which interfere with the cell's protection from radiation harm [20]. Bryostatin enhances the development of advanced stem cells in mouse bone marrow, i.e. it enhances repairs in bone marrow after exposure to radiation [21].
However, other studies have indicated that protein kinase activators have a role in the apoptosis induced by irradiation through ATM; it inhibits the production of ceramide, which prevents the cell from getting into apoptosis, where PKCa causes a reregulation or negative regulation of ATM proteins. The negative regulation forces cells to enter the stage of apoptosis but does not cause real apoptosis. In addition to passive regulation of ATM, the apoptosis needs radiation [22].
The role of ZFN, Exposure to radiation causes an increase in p53, resulting from the break-up of DNA. P53 then phosphorylates many of its target genes, including BAX and PUMA, which are sufficient to cause cell death [23]. Here the role of ZFN is clear, as it cuts off both BAX and BAK, and thus decreases in apoptotic proteins and reduces cell death [24].
Antiviral Drugs, It has been previously indicated that antiviral drugs cause the depletion of mitochondrial DNA, subsequently depleting DHODH, reducing pyrimidine concentrations and decreasing lymphatic reproduction [25]. So The decrease in lymphatic production includes both CD4 and CD8 i.e. decrease in the entire proportion, this is observed in clinical trials in which patients took didanosine, which is from (NRTIs), and this is what our results show [25].