Establishing Pediatric Mouse Models of the Hematopoietic Acute Radiation Syndrome and the Delayed Effects of Acute Radiation Exposure.

Medical countermeasures (MCMs) for hematopoietic acute radiation syndrome (H-ARS) should be evaluated in well-characterized animal models, with consideration of at-risk populations such as pediatrics. We have developed pediatric mouse models of H-ARS and delayed effects of acute radiation exposure (DEARE) for efficacy testing of MCMs against radiation. Male and female C57BL/6J mice aged 3, 4, 5, 6, 7 and 8 weeks old (±1 day) were characterized for baseline hematopoietic and gastrointestinal parameters, radiation response, efficacy of a known MCM, and DEARE at six and 12 months after total-body irradiation (TBI). Weanlings (age 3 weeks) were the most radiosensitive age group with an estimated LD50/30 of 712 cGy, while mice aged 4 to 8 weeks were more radioresistant with an estimated LD50/30 of 767-787 cGy. Female weanlings were more radiosensitive than males at 3 and 4 weeks old but became significantly more radioresistant after the pubertal age of 5 weeks. The most dramatic increase in body weight, RBC counts and intestinal circumference length occurred from 3 to 5 weeks of age. The established radiomitigator Neulasta® (pegfilgrastim) significantly increased 30-day survival in all age groups, validating these models for MCM efficacy testing. Analyses of DEARE among pediatric survivors revealed depressed weight gain in males six months post-TBI, and increased blood urea nitrogen at 12 months post-TBI which was more severe in females. Hematopoietic DEARE at six months post-TBI appeared to be less severe in survivors from the 3- and 4-week-old groups but was equally severe in all age groups by 12 months of age. Similar to our other acute radiation mouse models, there was no appreciable effect of Neulasta used as an H-ARS MCM on the severity of DEARE. In summary, these data characterize a pediatric mouse model useful for assessing the efficacy of MCMs against ARS and DEARE in children.

Global dynamics of healthy and cancer cells competing in the hematopoietic system.

Stem cells in the bone marrow differentiate to ultimately become mature, functioning blood cells through a tightly regulated process (hematopoiesis) including a stem cell niche interaction and feedback through the immune system. Mutations in a hematopoietic stem cell can create a cancer stem cell leading to a less controlled production of malfunctioning cells in the hematopoietic system. This was mathematically modelled by Andersen et al. (2017) including the dynamic variables: healthy and cancer stem cells and mature cells, dead cells and an immune system response. Here, we apply a quasi steady state approximation to this model to construct a two dimensional model with four algebraic equations denoted the simple cancitis model. The two dynamic variables are the clinically available quantities JAK2V617F allele burden and the number of white blood cells. The simple cancitis model represents the original model very well. Complete phase space analysis of the simple cancitis model is performed, including proving the existence and location of globally attracting steady states. Hence, parameter values from compartments of stem cells, mature cells and immune cells are directly linked to disease and treatment prognosis, showing the crucial importance of early intervention. The simple cancitis model allows for a complete analysis of the long term evolution of trajectories. In particular, the value of the self renewal of the hematopoietic stem cells divided by the self renewal of the cancer stem cells is found to be an important diagnostic marker and perturbing this parameter value at intervention allows the model to reproduce clinical data. Treatment at low cancer cell numbers allows returning to healthy blood production while the same intervention at a later disease stage can lead to eradication of healthy blood producing cells. Assuming the total number of white blood cells is constant in the early cancer phase while the allele burden increases, a one dimensional model is suggested and explicitly solved, including parameters from all original compartments. The solution explicitly shows that exogenous inflammation promotes blood cancer when cancer stem cells reproduce more efficiently than hematopoietic stem cells.

Chronic Stress-Related Neural Activity Associates With Subclinical Cardiovascular Disease in Psoriasis: A Prospective Cohort Study.

OBJECTIVES: This study hypothesized that there is an association between chronic stress (as indexed by resting amygdalar activity [AmygA]), hematopoietic system activity (HMPA), and subclinical cardiovascular indexes (aortic vascular inflammation [VI] and noncalcified coronary plaque burden [NCB]) in psoriasis (PSO). The study also hypothesized that treatment of PSO would improve these parameters. BACKGROUND: PSO is a stress-related chronic inflammatory condition that is associated with increased prevalence of subclinical cardiovascular disease (CVD). In individuals without PSO, stress has been linked to CVD through a serial biological pathway that involves the amygdala, hematopoietic tissues, and atherosclerotic plaques. METHODS: A total of 164 consecutive patients with PSO and 47 healthy volunteers underwent 18-fluorodeoxyglucose positron emission tomography/computed tomography scans for assessment of AmygA, HMPA, and VI, as well as coronary computed tomography angiography scans for quantifying NCB. Furthermore, a consecutive subset of 30 patients with severe PSO (Psoriasis Area Severity Index Score >10) were followed at 1 year to assess the relationship between skin disease improvement and AmygA, HMPA, VI, and NCB. RESULTS: The PSO cohort was middle-aged (mean age: 50 years), had low cardiovascular risk (Framingham risk score: median: 3) and had mild to moderate PSO activity (median Psoriasis Area Severity Index Score: 5.6). AmygA was higher in patients with PSO compared to volunteer participants. AmygA was associated with HMPA (bone marrow activity: ß = 0.20, p = 0.01) and subclinical CVD (VI: ß = 0.31, p < 0.001; NCB: ß = 0.27, p < 0.001) The AmygA-CVD association was in part mediated by HMPA (VI: 20.9%, NCB: 36.7%). Following 1 year of PSO treatment in those with severe disease, improvement in skin disease was accompanied by a reduction in AmygA, bone marrow activity, and VI, with no progression of NCB. CONCLUSIONS: In PSO, a chronic inflammatory disease state, AmygA, which is a manifestation of chronic stress, substantially contributes to the risk of subclinical CVD. Additional studies that use psychometric measures of stress are required to explore therapeutic impact.

Hematological alterations in protein malnutrition.

Protein malnutrition is one of the most serious nutritional problems worldwide, affecting 794 million people and costing up to $3.5 trillion annually in the global economy. Protein malnutrition primarily affects children, the elderly, and hospitalized patients. Different degrees of protein deficiency lead to a broad spectrum of signs and symptoms of protein malnutrition, especially in organs in which the hematopoietic system is characterized by a high rate of protein turnover and, consequently, a high rate of protein renewal and cellular proliferation. Here, the current scientific information about protein malnutrition and its effects on the hematopoietic process is reviewed. The production of hematopoietic cells is described, with special attention given to the hematopoietic microenvironment and the development of stem cells. Advances in the study of hematopoiesis in protein malnutrition are also summarized. Studies of protein malnutrition in vitro, in animal models, and in humans demonstrate several alterations that impair hematopoiesis, such as structural changes in the extracellular matrix, the hematopoietic stem cell niche, the spleen, the thymus, and bone marrow stromal cells; changes in mesenchymal and hematopoietic stem cells; increased autophagy; G0/G1 cell-cycle arrest of progenitor hematopoietic cells; and functional alterations in leukocytes. Structural and cellular changes of the hematopoietic microenvironment in protein malnutrition contribute to bone marrow atrophy and nonestablishment of hematopoietic stem cells, resulting in impaired homeostasis and an impaired immune response.

Multiparametric Imaging of Organ System Interfaces.

Cardiovascular diseases are a consequence of genetic and environmental risk factors that together generate arterial wall and cardiac pathologies. Blood vessels connect multiple systems throughout the entire body and allow organs to interact via circulating messengers. These same interactions facilitate nervous and metabolic system's influence on cardiovascular health. Multiparametric imaging offers the opportunity to study these interfacing systems' distinct processes, to quantify their interactions, and to explore how these contribute to cardiovascular disease. Noninvasive multiparametric imaging techniques are emerging tools that can further our understanding of this complex and dynamic interplay. Positron emission tomography/magnetic resonance imaging and multichannel optical imaging are particularly promising because they can simultaneously sample multiple biomarkers. Preclinical multiparametric diagnostics could help discover clinically relevant biomarker combinations pivotal for understanding cardiovascular disease. Interfacing systems important to cardiovascular disease include the immune, nervous, and hematopoietic systems. These systems connect with classical cardiovascular organs, such as the heart and vasculature, and with the brain. The dynamic interplay between these systems and organs enables processes, such as hemostasis, inflammation, angiogenesis, matrix remodeling, metabolism, and fibrosis. As the opportunities provided by imaging expand, mapping interconnected systems will help us decipher the complexity of cardiovascular disease and monitor novel therapeutic strategies.

[Role of SOX7 in Hematopoietic System Development and Hematological Malignancies--Review].

The sex-determining region Y-box 7 (Sox7) is a important member of SOX family containing high mobi- lity group (HMG), mapped to human chromosome 8p23.1. Wnt/ß-catenin signaling pathway plays an important role in cell survival, differentiation, self-renewal, proliferation and apoptosis, and is closely related with carcinogenesis. SOX7 gene is likely to be a tumor suppressor gene in MDS and other hematological malignancies. As a negative regulator of the WNT/ß-catenin signaling pathway, the function loss of this gene can lead to carcinogenesis. The methylation of SOX7 gene leads to the silence of this gene, resulting in tumorigenesis. The decision of hematopoietic stem cells to self-renew or differentiate is a stochastic process, but SOX7 can promote the differentiation into all blood cell types. This review focuses on the role of SOX7 in hematopoietic system development and hematological malignancies.

Recuento absoluto de linfocitos como factor predictivo en el trasplante hematopoyético / Absolute lymphocyte count as a predictor in hematopoietic transplantation

La recuperación temprana de linfocitos es un factor pronóstico que está relacionado con una mayor supervivencia libre de eventos y supervivencia global en pacientes trasplantados. Se realizó una revisión bibliográfica con el objetivo de determinar el valor pronóstico del recuento absoluto de linfocitos en pacientes con hemopatías malignas, tratados con trasplante. Los pacientes con trasplantes autólogos alcanzan un recuento absoluto de linfocitos el día + 15 (RAL15) e 500 x mm³, más temprano que los alogénicos. El RAL15 cuando se utiliza sangre periférica es mayor que cuando se emplea la médula ósea. Los factores pronósticos asociados a una peor supervivencia global fueron la sepsis, el RAL15 < 500x mm³ y la recaída. Varios estudios muestran una mejor supervivencia global y supervivencia libre de eventos a los cinco años, en los pacientes con RAL15 e 500 x mm³. El RAL15 e 500 x mm³ es una herramienta simple y útil para predecir un mejor resultado en pacientes sometidos a trasplante hematopoyético

Early recovery of lymphocytes is a prognostic factor that is related to a higher event-free survival and overall survival after haematopoietic stem cell transplantation. A literature review was conducted in order to determine the prognostic value of absolute lymphocyte count in patients with hematological malignancies after transplantation. Autologous transplant patients reach an absolute lymphocyte count on day + 15 (RAL15) e 500 x mm³, earlier than allogeneic. The RAL15 when peripheral blood is used is greater than when using the bone marrow. Prognostic factors associated with worse overall survival were sepsis, RAL 15 <500x mm³ and relapse. Several studies show a better overall survival and event-free survival at five years in patients with e 500 x RAL15 mm³. The RAL15 e 500 x mm³ is a simple and useful tool to predict a better outcome in patients undergoing hematopoietic transplantation

Defective autophagy in fibroblasts may contribute to fibrogenesis in autoimmune processes.

Fibrosis may represent the final step induced by autoimmune mechanism(s). This may be due to the excess in fibroblast recruitment, activation and differentiation in myofibroblasts. These events may be triggered by cytokines, chemokines and growth factors released by lymphocytes or macrophages. Autophagy is an essential conserved homeostatic process that has long been appreciated for cell adaptation to nutrient deprivation. Autophagy is also recognized as an important component of both innate and acquired immunity to pathogens. Recently, dysregulation of autophagy in haematopoietic cells has been suggested to amplify the autoimmune responses. On the other hand, it is possible that defective autophagy in non-haematopoietic cells contributes to the progression to fibrosis. In fibroblasts some alterations in the metabolic pathways and pharmacological data suggest that a defective autophagy could contribute to excess in the production of extracellular matrix by altering the turnover of protein such as collagen. Our goal in this review is to describe the current knowledge on the role of autophagy in the development of fibrotic autoimmune diseases. Further studies could confirm whether agents modulating autophagy may be used in the treatment of these autoimmune diseases.

Rac GTPases in human diseases.

Rho GTPases are members of the Ras superfamily of GTPases that regulate a wide variety of cellular functions. While Rho GTPase pathways have been implicated in various pathological conditions in humans, to date coding mutations in only the hematopoietic specific GTPase, RAC2, have been found to cause a human disease, a severe phagocytic immunodeficiency characterized by life-threatening infections in infancy. Interestingly, the phenotype was predicted by a mouse knock-out of Rac2 and resembles leukocyte adhesion deficiency (LAD). Here we review Rho GTPases with a specific focus on Rac GTPases. In particular, we discuss a new understanding of the unique and overlapping roles of Rac2 in blood cells that has developed since the generation of mice deficient in Rac1, Rac2 and Rac3 proteins. We propose that Rac2 mutations leading to disease be termed LAD type IV.

[Tissue reactions under chronic exposure to ionizing radiation].

The overview presents an outline of the radiobiological mechanisms governing the origin of tissue reactions manifested by a number of systems influencing the course and the outcomes of chronic exposure of man. The issues under consideration include the key mechanisms of tissue reactions and adaptation in response to a long-term and fractionated exposure to ionizing radiation. The response of the hemopoietic, of immune, of genital, of endocrine, of respiratory systems and of the skin to chronic radiation is described. The development of a new approach to threshold dose estimation for chronic exposure effects is discussed.

Ingeniería tisular: aplicación de las células troncales pluripotenciales en cirugía ortopédica y traumatológica / Tissue engineering: application of pluripotent stem cells in traumatology and orthopedic surgery

La ingeniería de tejidos en cirugía ortopédica está adquiriendo mayor auge y su aplicación clínica es una realidad aunque se desconocen sus posibilidades reales. Inicialmente se comenzaron a utilizar matrices, posteriormente factores de crecimiento y, más recientemente, células cultivadas o aspiradas de médula ósea. Se revisan las características de las células mesenquimales pluripotenciales y sus aplicaciones clínicas (AU)

Tissue engineering in orthopedic surgery is becoming increasingly popular, and its clinical application is a fact though the true possibilities of the technique are not known. Matrixes were initially used, followed by growth factors and, more recently, cultured cells or cells obtained from bone marrow aspirates. A review is made of the characteristics of pluripotent mesenchymal cells and their clinical applications (AU)

Hematopoietic response of rats exposed to the impact of an acute psychophysiological stressor on responsiveness to an in vivo challenge with Listeria monocytogenes: modulation by Chlorella vulgaris prophylactic treatment.

In this study, we investigated the hematopoietic response of rats pretreated with CV and exposed to the impact of acute escapable, inescapable or psychogenical stress on responsiveness to an in vivo challenge with Listeria monocytogenes. No consistent changes were observed after exposure to escapable footshock. Conversely, the impact of uncontrollable stress (inescapable and psychogenical) was manifested by an early onset and increased severity and duration of myelossuppression produced by the infection. Small size CFU-GM colonies and increased numbers of clusters were observed, concurrently to a greater expansion in the more mature population of bone marrow granulocytes. No differences were observed between the responses of both uncontrollable stress regimens. CV prevented the myelossuppression caused by stress/infection due to increased numbers of CFU-GM in the bone marrow. Colonies of cells tightly packed, with a very condensed nucleus; in association with a greater expansion in the more immature population of bone marrow granulocytes were observed. Investigation of the production of colony-stimulating factors revealed increased colony-stimulating activity (CSA) in the serum of normal and infected/stressed rats treated with the algae. CV treatment restored/enhanced the changes produced by stress/infection in total and differential bone marrow and peripheral cells counts. Further studies demonstrated that INF-gamma is significantly reduced, whereas IL-10 is significantly increased after exposure to uncontrollable stress. Treatment with CV significantly increased INF-gamma levels and diminished the levels of IL-10. Uncontrollable stress reduced the protection afforded by CV to a lethal dose of L. monocytogenes, with survival rates being reduced from (50%) in infected rats to 20% in infected/stressed rats. All together, our results suggest Chlorella treatment as an effective tool for the prophylaxis of post-stress myelossupression, including the detrimental effect of stress on the course and outcome of infections.

Osteoporosis of hematologic etiology.

OBJECTIVE: Here we present evidence that overexertion of the hematopoietic system following chronic bleeding plays an important role in the etiology of osteoporosis. MATERIALS AND METHODS: C57BL/6 mice were exposed to chronic bloodletting (0.2 mL twice per month for 10 months), total body irradiation (900 cGy), or aging (20-30 months old). Bone marrow from standard untreated donors was transplanted under the kidney capsules of all three categories of recipients to investigate the influence of each of these conditions on new bone marrow formation. Cellularity and histologic structure of developed osteohematopoietic sites and histomorphometry of lumbar vertebrae were studied, thus assessing the role of bleeding, irradiation, and old age on new bone formation and effects on existing bone. RESULTS: Chronic blood loss led to augmented production of hematopoietic microenvironment, relative reduction in the amount of generated bone, and activation of the bone resorptive process in the newly forming osteohematopoietic complex. Similar results were seen in irradiated and senescent mice. Activity, stimulating expansion of hematopoietic microenvironment, was revealed in the plasma of all three categories of experimental mice. Likewise, quantification of the relative amount of bone and hematopoietic areas in skeletal sites showed a significant reduction in bone tissue of the first lumbar vertebrae of chronically bled mice. CONCLUSIONS: Our experimental data, together with existing clinical observations documenting the role of hematopoietic insufficiency in the development of osteoporosis, confirm our working hypothesis that chronic blood loss may be the primary factor responsible for the rapid and consistent development of postmenopausal osteoporosis.

Early changes in organ function predict eventual survival in severe sepsis.

OBJECTIVE: Early identification and treatment of severe sepsis can significantly reduce mortality rate. We hypothesized that a risk prediction model based on early (baseline to day 1 of study) response to standard care should be significantly related to 28-day survival. DESIGN: Analysis of organ dysfunction data from two placebo-controlled severe sepsis trials (PROWESS and secretory phospholipase A2 inhibitor trials). SETTING: Research laboratory. PATIENTS: The placebo arms of two randomized, double-blind sepsis trials were combined (n = 1036). These patients met criteria for severe sepsis and received supportive standard intensive care and fluid resuscitation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sequential Organ Failure Assessment (SOFA) scores were calculated daily using the most aberrant physiologic or laboratory variables. Baseline and post-baseline SOFA scores categorized as improved, unchanged, or worsened were used in regression analyses correlating organ dysfunction changes with 28-day mortality. Improvement in cardiovascular (p = .0010), renal (p < .0001), or respiratory (p = .0469) function from baseline to day 1 was significantly related to survival. Odds ratios (95% confidence intervals) associated with improved vs. worsened respiratory, cardiovascular, or renal function before start of day 1 were 0.56 (0.35-0.91), 0.33 (0.18-0.59), and 0.30 (0.17-0.52), respectively. Continued improvement in cardiovascular function before start of day 2 and start of day 3 was associated with further improvement in survival (p <. 0001), with odds ratios of 0.15 (0.06-0.39) and 0.11 (0.04-0.31) for patients who improved compared with those who worsened. No other organ system was retained in the model, and improvement beyond day 1 in any other organ function did not add to the model's predictive power. CONCLUSIONS: These analyses suggest that outcomes for patients with severe sepsis are closely related to early (baseline to day 1 here) improvement, or lack thereof, in organ function. Also, clinical improvement on subsequent days may have little additional impact on the likelihood of survival.

[Dysregulation pathology of hemopoietic and immune systems under infectious process]. / Dizreguliatsionnaia patologiia krovetvornoi i immunnoi sistem pri infektsionnom protsesse.

Blood system and immune system play the crucial role in maintenance of anti-infectious defence of macroorganism. Meanwhile, infectious agents, differencing by their nature, have marked mutafacient effect on immunocompetent cells of blood. Dysregulation of DNK-reparation systems, apoptosis and immunity, maintaining genetic homeostasis of organism, is considered to be the basic reason of cytogenetic instability under infectious process. It has been established, that disturbances in blood and immunity systems, following infectious process, are caused by not only direct or indirect action of infectious agents on mature immunocytes, but else by their stimulating or suppressed influence on functional properties of early cells-precursors of hemo- and immunopoesis and hemopoietic microenvironment.

Perinatal dioxin exposure and later effects--a review.

Negative effects of perinatal exposure to background levels of dioxins and PCBs in Europe and the USA have been documented. Four facets of development are reviewed in this paper: 1. Brain development and thyroid hormone metabolism. 2. Hepatic effects. 3. Hematopoietic system effects. 4. Lung function. Effects on IQ and behaviour have been documented in children on both sides of the Atlantic Ocean. Non-dioxin-like PCBs, measured in maternal and cord blood and current plasma samples have been implicated. Interference with thyroid hormone metabolism in the mother, in the foetus and in the newborn baby could be responsible for these effects on brain development. During early gestation the foetus is completely dependent on maternal thyroxine (T4). Lower T4 levels in the mother, caused by dioxins and PCBs, might negatively influence (early) brain development. It is plausible that the intrauterine dependency on maternal T4 and the high T4 need shortly after birth makes both these periods vulnerable for environmental influences. Effects of dioxin exposure on thyroid hormone metabolism have been described in the period shortly after birth. These effects are no longer found after two years of age indicating a transient effect. In animal studies, in utero exposure has led to effects on brain development due to abnormal induction of liver enzymes. This induction resulted in lower testosterone and estrogen levels, interfering with brain development in the vulnerable period of language development and the development of visuo-spatial abilities. In humans this developmental period occurs around the thirtieth week of pregnancy. Follow-up studies in puberty and adolescence of the different cohorts studied is necessary to evaluate these negative influences. Damaging effects on the liver found shortly after birth have proven to be transient. Effects on the haematopoietic system are clear immediately after birth, for instance on white blood cells and thrombocytes. An increase in middle ear infections (otitis media) in relation to current levels of PCBs at the age of 4 years was described in the Rotterdam study. Negative effects on lung function in the sense of increased obstruction was found after 8 years in relation to perinatal exposure to dioxins in the Zaandam study. This rather new finding might explain the sharp increase in lung problems in children in the Western world.

[The role of apoptosis in the pathogenesis and treatment of neoplastic disorders of the hematopoietic system]. / Rola apoptozy w patogenezie i leczeniu nowotworów ukladu hematopoetycznego.

Defects in apoptotic cell-death regulation contribute to many disorders. Insufficient apoptosis leads to neoplastic and autoimmune disorders and chronic infections. Enhanced apoptosis is a cause of neurodegenerative disorder and complicates processes of ischemia. Genetic changes involving oncogenes and tumor suppressor genes contribute to the unregulated expansion of malignant cells. While some of these changes result in increased proliferation, others contribute to increasing cell numbers by inhibiting apoptosis. Because cytotoxic drugs or irradiation result in cell death by apoptosis, the genetic changes underlying malignancy often reduce the ability of these agents to destroy malignant cells. Knowledge of the molecular mechanisms of apoptosis provides insight into the causes of multiple pathologies where aberrant cell-death regulation occurs and provides new approaches to the treatment of human diseases.

[Quantitative and functional changes of T helper cell subsets in the bone marrow of severe aplastic anemia patients].

OBJECTIVE: To evaluate the quantitative and functional changes of T helper (Th) cell subsets in the bone marrow of severe aplastic anemia (SAA) patients and the relationship between these changes and the patients hematopoietic function. METHODS: By FACS, the quantity and ratio of Th1 and Th2 cells, the percentage of CD3(+)CD8(+) cells in the bone marrow were detected in 24 patients with SAA at active phase, 15 patients with SAA at recovery phase, and 16 normal controls. By radioimmunoassay, the serum levels of TNF-alpha, or IL-4 in 20 SAA patients at active phase, 12 at recovery phase and 16 normal controls were measured. The relationships between CD3(+)CD8(+) cells, TNF-alpha and Ret, ANC; and between Th1 cells and CD3(+)CD8(+) cells, TNF-alpha or Ret, ANC; between IL-4, balance of Th1/Th2 and Ret, ANC were evaluated. RESULTS: The percentages of Th1 and Th2 cells, and ratio of Th1/Th2 in bone marrow of SAA patients at active phase were (4.87 +/- 2.64)%, (0.41 +/- 0.26)% and 21.22 +/- 5.07, respectively, being higher than those of normal controls [(0.42 +/- 0.30)% (P < 0.01), (0.24 +/- 0.17)% (P < 0.05) and (1.57 +/- 0.93) (P < 0.01), respectively] and all of them reduced to normal levels of SAA at recovery phase (P > 0.05). The percentage of CD3(+)CD8(+) cells significantly decreased from (32.32 +/- 8.69)% at active phase to (13.76 +/- 2.96)% at recovery phase (P < 0.01). The serum levels of TNF-alpha and IL-4 at active phase was (4.29 +/- 3.15) microg/L and (1.24 +/- 0.73) microg/L, respectively, being higher than those of normal controls (1.21 +/- 1.16) microg/L, (1.18 +/- 0.97) microg/L, but only the difference of TNF-alpha was statistically significant (P < 0.01). In recovery SAA patients, the serum levels of TNF-alpha significantly decreased to (1.46 +/- 1.41) microg/L (P < 0.01), and the levels of IL-4 increased markedly to (3.05 +/- 1.94) microg/L. The CD3(+)CD8(+) cells and TNF-alpha of patients negatively correlated with Ret (P < 0.05; P < 0.05) and ANC (P < 0.05; P < 0.05), Th1 cells correlated with CD3(+)CD8(+) cells and TNF-alpha positively (P < 0.01; P < 0.05), the Ret and ANC negatively (P < 0.01; P < 0.01), IL-4 and the balance of Th1/Th2 positively correlated with Ret and ANC (P < 0.05, P < 0.01; P < 0.01, P < 0.01). CONCLUSION: The bone marrow failure in SAA might be caused not only by the increase of Th1 cells, Th1 type effector cells and cytokines, but also by insufficient compensation of Th2 cells and Th2 type cytokines, which shifted the balance of Th1/Th2 favorable to Th1.