Cancer immunotherapy by immunosuppression

We have previously suggested that the stimulatory effect of a weak immune reaction on tumor growth may be necessary for the growth of incipient tumors. In the present paper, we enlarge upon and extend that idea by collecting evidence in the literature bearing upon this new hypothesis that a growing cancer, whether in man or mouse, is throughout its lifespan, probably growing and progressing because of continued immune stimulation by a weak immune reaction. We also suggest that prolonged immunosuppression might interfere with progression and thus be an aid to therapy. While most of the considerable evidence that supports the hypothesis comes from observations of experimental mouse tumors, there is suggestive evidence that human tumors may behave in much the same way, and as far as we can ascertain, there is no present evidence that necessarily refutes the hypothesis

The role of polyclonal intravenous immunoglobulin in treating HIV-infected children with severe bacterial infections: A retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>Mortality among HIV-infected children in developing countries remains high after serious bacterial infections despite the use of antibiotics. Intravenous immunoglobulin (IVIG) has been used as an adjuvant therapy to treat these infections, but little data exists regarding its efficacy, and previous studies have focused on IVIG as a prophylactic agent. We examined the impact of IVIG as an adjuvant therapy in reducing mortality and length of hospital stay in HIV-infected children with serious bacterial infections.</p> <p>Methods</p> <p>This retrospective study focused on pediatric admissions at a large urban hospital between 2002 and 2006. Children between the ages of one month and nine years of age with laboratory confirmed HIV-status, serious bacterial infection, no prior exposure to IVIG, and a hospital length of stay of 5 days or more, were eligible for inclusion.</p> <p>Results</p> <p>A total of 140 children (median age 1.2 years) met inclusion criteria; lower respiratory tract infection was diagnosed in 94 (67%) of the children, while 74 (53%) had bacterial sepsis. Fifty-four (39%) children were receiving antiretroviral therapy and 39 (28%) were receiving tuberculosis treatment. Overall 73 (52%) were treated with IVIG, with the majority (74%) of children receiving a single dose. Thirteen (9%) died during their hospital admission. In crude analysis IVIG was significantly associated with increased mortality was (Odds Ratio (OR): 5.8; 95% Confidence Interval (CI): 1.2–27.1) and this association was weakened by adjustment for other predictors of mortality (OR 4.3, 95% CI 0.7–27.9, p = 0.123). IVIG use was also associated with longer hospital stays.</p> <p>Conclusion</p> <p>Administration of one to three doses of IVIG during the acute phase of illness does not appear to reduce mortality or the length of hospital stays in HIV-infected children with serious bacterial infections. However, the retrospective nature of this study makes confounding by indication difficult to control and further studies regarding the timing, dosing, and method of administration are required. Nonetheless the routine use of IVIG in resource-limited settings should be carefully considered given its high cost.</p

Lymphocyte subsets in human immunodeficiency virus-unexposed Brazilian individuals from birth to adulthood

Ethnic origin, genetics, gender and environmental factors have been shown to influence some immunologic indices, so that development of reference values for populations of different backgrounds may be necessary. We have determined the distribution of lymphocyte subsets in healthy Brazilian individuals from birth to adulthood. Lymphocyte subsets were determined using four-colour cytometry in a cross-sectional study of 463 human immunodeficiency virus-unexposed children and adults from birth through 49 years of age. Lymphocyte subsets varied according to age, as previously observed in other studies. However, total CD4+ T cell numbers were lower than what was described in the Pediatric AIDS Clinical Trials Group P1009 (PACTG P1009), which assessed an American population of predominantly African and Hispanic backgrounds until the 12-18 year age range, when values were comparable. Naïve percentages and absolute values of CD8+ T cells, as assessed by CD45RA expression, were also lower than the PACTG P1009 data for all analysed age ranges. CD38 expression on both CD4+ and CD8+ T cells was lower than the PACTG P1009 values, with a widening gap between the two studies at older age ranges. Different patterns of cell differentiation seem to occur in different settings and may have characteristic expression within each population.Universidade Federal de São Paulo (UNIFESP) Departamento de MedicinaCentro Assistencial Cruz de MaltaUniversidade Federal de São Paulo (UNIFESP) Departamento de PediatriaUNIFESP, Depto. de MedicinaUNIFESP, Depto. de PediatriaSciEL

Symptomatic hypogammaglobulinemia in infancy and childhood – clinical outcome and in vitro immune responses

BACKGROUND: Symptomatic hypogammaglobulinemia in infancy and childhood (SHIC), may be an early manifestation of a primary immunodeficiency or a maturational delay in the normal production of immunoglobulins (Ig). We aimed to evaluate the natural course of SHIC and correlate in vitro lymphoproliferative and secretory responses with recovery of immunoglobulin values and clinical resolution. METHODS: Children, older than 1 year of age, referred to our specialist clinic because of recurrent infections and serum immunoglobulin (Ig) levels 2 SD below the mean for age, were followed for a period of 8 years. Patient with any known familial, clinical or laboratory evidence of cellular immunodeficiency or other immunodeficiency syndromes were excluded from this cohort. Evaluation at 6- to 12-months intervals continued up to 1 year after resolution of symptoms. In a subgroup of patients, in vitro lymphocyte proliferation and Ig secretion in response to mitogens was performed. RESULTS: 32 children, 24 (75%) males, 8 (25%) females, mean age 3.4 years fulfilled the inclusion criteria. Clinical presentation: ENT infections 69%, respiratory 81%, diarrhea 12.5%. During follow-up, 17 (53%) normalized serum Ig levels and were diagnosed as transient hypogammaglobulinemia of infancy (THGI). THGI patients did not differ clinically or demographically from non-transient patients, both having a benign clinical outcome. In vitro Ig secretory responses, were lower in hypogammaglobulinemic, compared to normal children and did not normalize concomitantly with serum Ig's in THGI patients. CONCLUSIONS: The majority of children with SHIC in the first decade of life have THGI. Resolution of symptoms as well as normalization of Ig values may be delayed, but overall the clinical outcome is good and the clinical course benign

The impact of maternal HIV infection on cord blood lymphocyte subsets and cytokine profile in exposed non-infected newborns

<p>Abstract</p> <p>Background</p> <p>Children born to HIV+ mothers are exposed intra-utero to several drugs and cytokines that can modify the developing immune system, and influence the newborn's immune response to infections and vaccines. We analyzed the relation between the distribution of cord blood lymphocyte subsets and cytokine profile in term newborns of HIV+ mothers using HAART during pregnancy and compared them to normal newborns.</p> <p>Methods</p> <p>In a prospective, controlled study, 36 mother-child pairs from HIV+ mothers and 15 HIV-uninfected mothers were studied. Hematological features and cytokine profiles of mothers at 35 weeks of pregnancy were examined. Maternal and cord lymphocyte subsets as well as B-cell maturation in cord blood were analyzed by flow cytometry. The non-stimulated, as well as BCG- and PHA-stimulated production of IL2, IL4, IL7, IL10, IL12, IFN-γ and TNF-alpha in mononuclear cell cultures from mothers and infants were quantified using ELISA.</p> <p>Results</p> <p>After one year follow-up none of the exposed infants became seropositive for HIV. An increase in B lymphocytes, especially the CD19/CD5+ ones, was observed in cord blood of HIV-exposed newborns. Children of HIV+ hard drug using mothers had also an increase of immature B-cells. Cord blood mononuclear cells of HIV-exposed newborns produced less IL-4 and IL-7 and more IL-10 and IFN-γ in culture than those of uninfected mothers. Cytokine values in supernatants were similar in infants and their mothers except for IFN-γ and TNF-alpha that were higher in HIV+ mothers, especially in drug abusing ones. Cord blood CD19/CD5+ lymphocytes showed a positive correlation with cord IL-7 and IL-10. A higher maternal age and smoking was associated with a decrease of cord blood CD4+ cells.</p> <p>Conclusions</p> <p>in uninfected infants born to HIV+ women, several immunological abnormalities were found, related to the residual maternal immune changes induced by the HIV infection and those associated with antiretroviral treatment. Maternal smoking was associated to changes in cord CD3/CD4 lymphocytes and maternal hard drug abuse was associated with more pronounced changes in the cord B cell line.</p

Evidence of HIV-1 adaptation to host HLA alleles following chimp-to-human transmission

<p>Abstract</p> <p>Background</p> <p>The cytotoxic T-lymphocyte immune response is important in controlling HIV-1 replication in infected humans. In this immune pathway, viral peptides within infected cells are presented to T-lymphocytes by the polymorphic human leukocyte antigens (HLA). HLA alleles exert selective pressure on the peptide regions and immune escape mutations that occur at some of the targeted sites can enable the virus to adapt to the infected host. The pattern of ongoing immune escape and reversion associated with several human HLA alleles has been studied extensively. Such mutations revert upon transmission to a host without the HLA allele because the escape mutation incurs a fitness cost. However, to-date there has been little attempt to study permanent loss of CTL epitopes due to escape mutations without an effect on fitness.</p> <p>Results</p> <p>Here, we set out to determine the extent of adaptation of HIV-1 to three well-characterized HLA alleles during the initial exposure of the virus to the human cytotoxic immune responses following transmission from chimpanzee. We generated a chimpanzee consensus sequence to approximate the virus sequence that was initially transmitted to the human host and used a method based on peptide binding affinity to HLA crystal structures to predict peptides that were potentially targeted by the HLA alleles on this sequence. Next, we used codon-based phylogenetic models to quantify the average selective pressure that acted on these regions during the period immediately following the zoonosis event, corresponding to the branch of the phylogenetic tree leading to the common ancestor of all of the HIV-1 sequences. Evidence for adaptive evolution during this period was observed at regions recognised by HLA A*6801 and A*0201, both of which are common in African populations. No evidence of adaptive evolution was observed at sites targeted by HLA-B*2705, which is a rare allele in African populations.</p> <p>Conclusion</p> <p>Our results suggest that the ancestral HIV-1 virus experienced a period of positive selective pressure due to immune responses associated with HLA alleles that were common in the infected human population. We propose that this resulted in permanent escape from immune responses targeting unconstrained regions of the virus.</p

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an ‘immature’ neonatal to a ‘mature’ adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation

Influence of sex, age, pubertal maturation and body mass index on circulating white blood cell counts in healthy European adolescents—the HELENA study

Percentiles 10th, 25th, 50th, 75th and 90th are presented for circulating white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils and basophils in healthy European adolescents (12.5–17.5 years, n = 405, 48.9 % boys), considering age, sex, puberty and body mass index (BMI). CD3+ (mature T cells), CD4+ (T helper), CD8+ (T cytotoxic), CD16+56+ (natural killer), CD19+ (B cells), CD3+CD45RA+, CD4+CD45RA+, CD8+CD45RA+ (naïve), CD3+CD45RO+, CD4+CD45RO+ and CD8+CD45RO+ (memory) lymphocytes were also analysed by immunophenotyping. Girls presented higher WBC, neutrophil, CD3+CD45RO+ and CD4+CD45RO+ cell counts and CD3+/CD19+ ratio, and lower CD3+CD45RA+ and CD4+CD45RA+ counts than boys. Age was associated with higher neutrophil counts and CD3+/CD19+, and lower CD19+ counts; in boys, with lower CD3+CD45RA+, CD4+CD45RA+ and CD8+CD45RA+ counts as well; in girls, with higher WBC, CD3+CD45RO+ and CD4+CD45RO+ counts. Pubertal maturation in boys was associated with lower WBC and lymphocyte counts; in girls, with higher basophil, CD3+CD45RO+ and CD4+CD45RO+ values. BMI was associated with higher WBC counts; in boys, also with higher lymphocyte counts; in girls, with higher neutrophil, CD4+, CD3+CD45RO+ and CD4+CD45RO+ counts. Conclusion: Our study provides normative values for circulating immune cells in adolescents, highlighting the importance of considering sex, age, pubertal maturation and BMI when establishing reference ranges for WBC in paediatric populations