الفهرس 
AcknowledgmentOnly 14 pages are availabe for public view
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Abstract
Lymphoid malignancies are clonal disorders of the immune system. Pediatric lymphoid malignancies have been grouped in 2 broad categories: Acute lymphoblastic leukemia and non Hodgkin lymphoma. ALL is the most common malignancy of the developmental age comprising 30% of all neoplastic diseases in childhood while NHL accounts for approximately 7% of cancers in children younger than 20 years.
Chemotherapy, which is the basic treatment modality in many neoplastic diseases, including lymphoproliferative malignancies, negatively influences the immunological system. It disturbs the immune function and increases susceptibility to infectious diseases. T lymphocytes (CD3+ cells) are considered the key regulators and effector cells for multiple cellular and humoral immune functions.
In our study, we determined T cell reconstitution in ALL and NHL pediatric patients at the 1st (group I), 6th (group II) and 12th (group III) months from starting therapeutic regimens of St. Jude Children Research Hospital Total Therapy Study XIIIB Protocol. Each group was subclassified into standard and high patients according to risk criteria: age, leucocytic count, CNS status, testicular leukemia, immunophenotyping and genetic study. Control group was chosen as apparently healthy children, age and sex matched.
The flow cytometer used for determination of the count of T cells including their subsets (helper and cytotoxic T cells) and T cell function which included cells that express the costimulatory molecule CD28, that express activation marker CD25 and cells that secrete signature cytokines, IFN-γ for Th1 lymphocytes and IL-4 for Th2 lymphocytes.
T cells absolute count of study groups showed lower values in comparison to controls. No such significant difference between study groups was noticed and also no significant difference between T cells count of HR patients and that of SR patients of the same study group. A DROP in T cells count of SR patients was noticed from 1st to 6th month of treatment followed by re increase at 12th month.
T cells include 2 main subsets, helper CD4+ and cytotoxic CD8+ cells. Helper T cells are considered the maestro of immune system as they help other immune cells. They are essential for B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages. Cytotoxic T cells are killer cells that are mainly capable of inducing the death of virus infected cells or tumor cells.
Helper and cytotoxic cells absolute count also showed a high significant decrease as compared to controls. A steady mild significant increase of helper T cells count from 1st to 6th to 12th months from starting treatment while in those of cytotoxic T cells the significant recovery occurred lately between the 6th and 12th months from starting treatment. As compared to controls, CD4/CD8 ratio showed lower values at 1st month from starting treatment which gradually increased to achieve a complete recovery at 12th month. CD4/CD8 ratio of SR recovered earlier than that of HR. Also a DROP in T cell subsets count was noticed at the 6th month of treatment followed by reincrease, unlike those of HR patients who showed a gradual elevation all over the study period.
In our study, we focused on the expression of the co-stimulatory molecule; CD28 molecules, a marker for functional T cells. CD28 binds to two ligands expressed on APCs, B7-1 and B7-2. Co-stimulation of the TCR plus CD28 dramatically augments IL-2 production. In our study, the expression of CD28+ molecule on T cells of all study groups showed a significant reduction when compared to that of controls and this reduction was more obvious in HR patients. The expression of both SR and HR patients showed a slow progressive rise over the study period.
T cell immune reconstitution is dependent upon the generation of new T cells from progenitors via thymopoiesis and peripheral expansion of residual mature lymphocytes by antigenic stimulation and homeostatic cytokines. In our study, impaired generation of CD27+CD45RA+ naïve T cells all over the study period was remarked as a high significant reduction of patients’ naïve T cells percentages as compared to that of controls was noticed.
To assess T cell function, stimulation of T cells is performed (using PMA and ionomycin in the presence of Brefeldin-A) and T cell activation could be confirmed by demonstration of activation marker such as CD25. In our study, a poor response to T cell activation was noticed as a high significant decrease of CD25 expression on T cells as compared to controls.
No specific surface marker used to distinguish helper T cells subsets. The two main subsets of helper T cells distinguished functionally by their signature cytokines; IFN-γ for Th1 lymphocytes and IL-4 for Th2 lymphocytes (Mosmann et al., 1989; Rostaing et al., 1997). The main role of IFN-γ is to maximize the killing efficacy of the macrophages which serve numerous roles in the effector phases of adaptive immune responses. IL-4 is also a key regulator in humoral and adaptive immunity as it promotes the differentiation of naïve T cells to Th2 cells and responsible for B cells class switching to IgE and IgG4.
Both CD4+IFN-γ+ and CD4+IL-4+ cells percentages showed marked reduction of high significance when compared to that of controls. The reduction of these cells may be explained as a reduction of Th1 and Th2 cells or impaired secretion of those cytokines from their specific cells. The reduction of IL-4 secretion is more obvious than that of IFN-γ which means a more defect in the function of Th2 cells as compared to Th1 cells and this could be generally translated as an impairment of immunity and specifically as a more impairment in the immunity against parasitic infections in comparison to immunity against other forms of infections such as bacterial, viral or fungal infections.