Types of immune response in acute infectious diseases

The author's concept on the system of self regulation of immune response is described. Four types of this response are proposed, which differ by total intensity of cytokine reaction, the development time as well as manifestation degree of non specific immunosuppression, and, most importantly, the profile of specific immune response to the antigens of the infective agent. These four types of immune response are closely linked with increased severity of clinical manifestations.     

Acute pancreatitis during L-asparaginase treatment in children with acute lymphoblastic leukemia

L-asparaginase (L-ASPA) has been put to a wide application in many therapeutic protocols, above all in the treatment of acute lymphoblastic leukemia (ALL). We presented three cases of acute pancreatitis in children with ALL induced by administration of L-ASPA preparations. Our observations revealed that ultrasound investigations are very useful in diagnosis and monitoring changes in the pancreas. The use of L-ASPA derivatives allows to decrease the toxic and allergic sequele resulting from the administration of the drug.     

Etiology and structure of infectious complications of cytostatic therapy in children with acute lymphoblastic leukemia and non-B-cell non-Hodgkin lymphomas

A retrospective analysis of medical histories with acute lymphoblast leucosis and non-B-cell non-Hodgkin lymphomas made it possible to reveal infectious complications of cytostatic therapy in 100% of children, namely: sepsis (0.3%), unidentified infection (12%), local infection (87.7%). Infectious complications of the cytopenic nature were localized mainly in the upper sections of the gastrointestinal tract and in upper respiratory tract. Bacterial infectious complications caused by opportunistic microorganisms with the prevalence of Gram positive flora, resistant to cephalosporins of generations I and II, occurred most frequently.     

Role of the host immune response in selection of equine infectious anemia virus variants.

Equine infectious anemia virus was isolated from peripheral blood leukocytes collected during two early febrile cycles of an experimentally infected horse. RNase T1-resistant oligonucleotide fingerprint analyses indicated that the nucleotide sequences of the isolates differed by approximately 0.25% and that the differences appeared randomly distributed throughout the genome. Serum collected in the interval between virus isolations was able to distinguish the isolates by membrane immunofluorescence on live cells. However, no neutralizing antibody was detected in the interval between virus isolations. In fact, multiple clinical cycles occurred before the development of a neutralizing antibody response, indicating that viral neutralization might not be the mechanism for selection of antigenic variants. The ability of early immune sera to recognize variant specific antigens on the surface of infected cells suggested that immune selection occurs through recognition and elimination of certain virus-infected cells. Alternately, the random distribution of the genomic differences observed between the two isolates may indicate that equine infectious anemia virus variants emerge as a result of nonimmunological selection processes.     

Decreased hormone content of immune cells in children during acute lymphocytic leukemia (ALL) - effect of treatment

Histamine, serotonin and triiodothyronine (T3) content of different circulating lymphocyte subsets of leukemic (acute lymphocytic leukemia, ALL) and non-leukemic (control) children were investigated by multicolor flow cytometry. The hormone contents of the cells were followed from the time of diagnosis till the end of treatment. Each hormone could be detected in every time in the investigated cell types, although the amounts of them changed during the treatment.T lymphocytes: Significantly lower amount of serotonin was found in each T cell subsets (Th, Tc and activated T lymphocytes) of leukemic children compared to the healthy control group at the time of diagnosis and it was permanently low during the maintenance therapy. The decreased amount of serotonin could be demonstrated in Tc and Th cells even at one year after the end of treatment. However, there was no alteration in the histamine and T3 content of T cell subsets in the time of diagnosis, but significant decrease was detected during the maintenance therapy and after treatment.NK cells: The serotonin and T3 contents of NK cells (both NK and NKT subsets) were significantly lower at the time of diagnosis and during the maintenance therapy. Similar decrease was detected in the case of serotonin in B cells. Although there was no difference in the T3 content of B cells at the time of diagnosis, significantly lower amounts could be detected during the therapy compared to the healthy control group. The serotonin concentration remained low for years after the end of treatment, both in B and NK cells. These observations might have diagnostic and prognostic importance.     

Allelic variants of polymorphic genes associated with a higher frequency of chromosome aberrations

Genotypic associations were studied for the frequency of chromosome aberrations in human peripheral blood lymphocytes. Cytogenetic analysis (1000 metaphase plate per individual) and genotyping at 19 sites of genes involved in detoxification and DNA repair were performed in a sample of 83 Chernobyl liquidators and a matched control sample of 96 volunteers. In either sample, the frequency of chromosome aberrations was higher in carriers of the minor alleles of the XPD gene (sites 2251T > G and 862G > A) and the positive genotypes of the GSTM1-GSTT1 genes. The highest frequency of chromosome aberrations was observed in carriers of a combined genotype including at least one minor allele of the XPD sites + at least one insertion in the GSTM1-GSTT1 genes. The high-risk genotype, which had a prevalence of 64%, was strongly associated with a higher frequency of chromosome aberrations in both volunteers (OR = 6.9, P = 0.008) and Chernobyl liquidators (OR = 5.6, P = 0.002).     

Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia

Almost two decades ago, the sequencing of the human genome and high throughput technologies came to revolutionize the clinical and therapeutic approaches of patients with complex human diseases. In acute lymphoblastic leukemia (ALL), the most frequent childhood malignancy, these technologies have enabled to characterize the genomic landscape of the disease and have significantly improved the survival rates of ALL patients. Despite this, adverse reactions from treatment such as toxicity, drug resistance and secondary tumors formation are still serious consequences of chemotherapy, and the main obstacles to reduce ALL-related mortality. It is well known that germline variants and somatic mutations in genes involved in drug metabolism impact the efficacy of drugs used in oncohematological diseases therapy. So far, a broader spectrum of clinically actionable alterations that seems to be crucial for the progression and treatment response have been identified. Although these results are promising, it is necessary to put this knowledge into the clinics to help physician make medical decisions and generate an impact in patients’ health. This review summarizes the gene variants and clinically actionable mutations that modify the efficacy of antileukemic drugs. Therefore, knowing their genetic status before treatment is critical to reduce severe adverse effects, toxicities and life-threatening consequences in ALL patients.     

Clinically conditional variants of the immune response in viral hepatitis A and B in children

The immunity characteristics of the T-, B- and A-systems have been studied on the basis of the data registered in the dynamics of the acute period of the disease and several times in catamnesis during 6-12 months of the convalescence period in 217 children with viral hepatitis A and 99 children with viral hepatitis B. The clinical course of viral hepatitis A and that of viral hepatitis B have been found to have certain parallels in their development, as well as specific features of immune response, which can be subdivided into 3 main groups: (a) immunological imbalance, (b) the phase of immunodepression and (c) secondary immunodeficiency. The distinguishing of the variants of immune response and their clinical interpretation are of practical importance for the early prognostication of the course and outcome of the processes and for the differentiated approach to the treatment of viral hepatitides in children.     

Expression profile of immune response genes during acute myopathy induced by chikungunya virus in a mouse model

During the recent re-emergence of chikungunya, clinical complications and deaths were recorded. Persistent musculoskeletal pain, arthralgia, arthritis were among the most common complications. To understand pathogenesis of CHIKV induced disease, we developed suckling, outbred mouse model presenting with severe myopathology. Histopathology, dynamics of viral load, IgG antibodies/isotypes, serum cytokines by cytometric bead array and mRNA expression levels of immune response genes in the target tissue by Taqman Low Density Array were studied. Peak viral load was associated with peak serum levels of CCL-2,KC, CCL-4, RANTES, IL-6, IL-10, CSF-3, and locally very high mRNA expression of CCL-2, CXCL-10, CXCL-11 and concomitant IFNγ, IL-10, STAT-1, SOCS-1 and CSF-3 suggesting strong IFNγ program. Symptomatic phase correlated with peak serum levels of IL-2, IFNγ, IL-17, CCL-3, IL-1β, eotaxin, IL-9 and CSF-2 and locally with peak mRNA expression of macrophage induced pro inflammatory cytokines and immune infiltration biased towards Th1. IgG antibodies were detected on day 6PI, reaching high titres by day 11PI. IgG2a was the predominant isotype, indicating Th1 bias. This is the first report of comprehensive analysis of immune response genes expression in target tissue of CHIKV mouse model. The data would contribute significantly in understanding pathogenesis of CHIKV disease and viral myopathies.     

Adjuvant immune stimulation with Corynebacterium parvum during maintenance chemotherapy of acute myeloid leukemia

Of 93 consecutively treated patients with acute myeloid leukemia 36 (39%) achieved complete remission (CR). Thirty-five patients were randomized to receive either maintenance chemotherapy alone (C) or a combination of active nonspecific immunotherapy with Corynebacterium parvum and chemotherapy (C + I). Maintenance therapy was given monthly for 1 year or until relapse. The median survival time was 21 months for patients treated with chemotherapy alone, compared with 30 months for patients treated with chemotherapy and immunotherapy. The median remission duration was 15 months for patients treated with chemotherapy, compared with 18 months for chemotherapy and immunotherapy group. While no statistically significant difference in remission duration or survival time could be attributed to the use of immune stimulation, a plateau of 40% long-term time survivors was defined in the chemotherapy and immunotherapy group. Age and sex were found to be the major prognostic factors for achievement of CR. No difference was found in remission duration or survival between the two different induction schedules. Neither did the morphological subtype of AML (FAB classification) or the leukocyte count at diagnosis correlate with remission rate or survival.     

Characteristics of immune response to diphtheria anatoxin in children with different immune status during the second age-scheduled revaccination

The dynamics of the intensity of specific antidiphtheria immunity after the second age-scheduled revaccination was studied in 129 practically healthy children. The study revealed that the formation of immunity depended on the initial functional state of the immune system before the injection of diphtheria toxoid. Three variants of immune response were determined and the immune status corresponding to each of these variants was characterized. As shown in this study, children with the hyperergic character of immune response were characterized by relatively high initial titers of antitoxin, and the injection of an additional dose of the antigen led to the prolonged state of hyperimmunization with the subsequent decrease of the intensity of immunity by half, registered in the catamnestic observation for 4 years. Children with the hypo- and normoergic variants of immune response were characterized by the most stable immune response to diphtheria toxoid, and during the catamnestic observation they formed the levels of antibody titers 2.5- to 3-fold higher than before immunization. But the protection characteristics in children with the third variant were the lowest among the children under study.     

Inflammatory response mediates cross-talk with immune function and reveals clinical features in acute myeloid leukemia

Accumulated genetic mutations are an important cause for the development of acute myeloid leukemia (AML), but abnormal changes in the inflammatory microenvironment also have regulatory effects on AML. Exploring the relationship between inflammatory response and pathological features of AML has implications for clinical diagnosis, treatment and prognosis evaluation. We analyzed the expression variation landscape of inflammatory response-related genes (IRRGs) and calculated an inflammatory response score for each sample using the gene set variation analysis (GSVA) algorithm. The differences in clinical- and immune-related characteristics between high- and low-inflammatory response groups were further analyzed. We found that most IRRGs were highly expressed in AML samples, and patients with high inflammatory response had poor prognosis and were accompanied with highly activated chemokine-, cytokine- and adhesion molecule-related signaling pathways, higher infiltration ratios of monocytes, neutrophils and M2 macrophages, high activity of type I/II interferon (IFN) response, and higher expression of immune checkpoints. We also used the Genomics of Drug Sensitivity in Cancer (GDSC) database to predict the sensitivity of AML samples with different inflammatory responses to common drugs, and found that AML samples with low inflammatory response were more sensitive to cytarabine, doxorubicin and midostaurin. SubMap algorithm also demonstrated that high-inflammatory response patients are more suitable for anti-PD-1 immunotherapy. Finally, we constructed a prognostic risk score model to predict the overall survival (OS) of AML patients. Patients with higher risk score had significantly shorter OS, which was confirmed in two validation cohorts. The analysis of inflammatory response patterns can help us better understand the differences in tumor microenvironment (TME) of AML patients, and guide clinical medication and prognosis prediction.     

Physiology of immune response genes

In addition to performing its major physiological function--a control of the immune response, the major gene complex: HLA system, also maintains a human genetic diversity. The latter provides optimal conditions for survival of human being as species. We submit modern data on genome and proteome mechanisms which are principal for maintenance of these functions.