Pronounced Immune Response Research Articles

Effect of temperature on production of skin mucus antibody in flounder (Paralichthys olivaceus)

We evaluated the effects of water temperature on the kinetics of skin mucus antibody in the flounder(Paralichthys olivaceus) using an indirect enzyme-linked immunosorbent assay(ELISA).The fish were held at 9℃,15℃,21℃,and 26℃ and given an intraperitoneal injection of inactivated lymphocystis disease virus(LCDV).The optical density(OD) of mucus antibody peaked 9 and 7 weeks after treatment in the groups held at 9℃ and 15℃,respectively(9℃: OD=0.179;15℃: OD=0.233).The OD increased most rapidly in fish held at 21℃,peak-ing at 0.316 during the 5th week.The OD was lower in fish held at 26℃ than at 21℃ and peaked(0.295) in the 5th week.We collected a sample of skin mucus from fish with the highest OD and extracted mucus Ig by ammo-nium sulfate precipitation.The mucus proteins from all four treatment groups yielded bands at 72 kD and 26 kD.Western blotting analysis revealed that the monoclonal antibody against serum Ig heavy chain could only recog-nize the 72 kD protein,which represents the heavy chain of skin mucus Ig.In conclusion,the most pronounced immune response was measured in fish that were maintained at their optimal temperature(21℃).In addition,the isolated mucus Ig may be used to study mucosal immunity in flounder.

Intra-Peritoneal Hyperthermia Combining α-Galactosylceramide in the Treatment of Ovarian Cancer

The purpose of this study was to investigate the anti-tumor effect and potential mechanisms of i.p. hyperthermia in combination with α-galactosylceramide (α-GalCer) for the treatment of ovarian cancer. In this study, immuno-competent tumor models were established using murine ovarian cancer cell lines and treated with i.p. hyperthermia combining α-GalCer. Th1/Th2 cytokine expression profiles in the serum, NK cell cytotoxicity and phagocytic activities of dendritic cells (DCs) were assayed. We also analyzed the number of CD8+/IFN-γ+ tumor specific cytotoxic T cells, as well as the tumor growth based on depletion of lymphocyte sub-population. Therapeutic effect on those ovarian tumors was monitored by a non-invasive luminescent imaging system. Intra-peritoneal hyperthermia induced significant pro-inflammatory cytokines expression, and sustained the response of NK and DCs induced by α-GalCer treatment. The combination treatment enhanced the cytotoxic T lymphocyte (CTL) immune response in two mouse ovarian cancer models. This novel treatment modality by combination of hyperthermia and glycolipid provides a pronounced anti-tumor immune response and better survival. In conclusion, intra-peritoneal hyperthermia enhanced the pro-inflammatory cytokine secretion and phagocytic activity of DCs stimulated by α-GalCer. The subsequent CTL immune response induced by α-GalCer was further strengthened by combining with i.p. hyperthermia. Both innate and adaptive immunities were involved and resulted in a superior therapeutic effect in treating the ovarian cancer.

Therapeutic Response in Feline Sandhoff Disease Despite Immunity to Intracranial Gene Therapy

Salutary responses to adeno-associated viral (AAV) gene therapy have been reported in the mouse model of Sandhoff disease (SD), a neurodegenerative lysosomal storage disease caused by deficiency of β-N-acetylhexosaminidase (Hex). While untreated mice reach the humane endpoint by 4.1 months of age, mice treated by a single intracranial injection of vectors expressing human hexosaminidase may live a normal life span of 2 years. When treated with the same therapeutic vectors used in mice, two cats with SD lived to 7.0 and 8.2 months of age, compared with an untreated life span of 4.5 ± 0.5 months (n = 11). Because a pronounced humoral immune response to both the AAV1 vectors and human hexosaminidase was documented, feline cDNAs for the hexosaminidase α- and β-subunits were cloned into AAVrh8 vectors. Cats treated with vectors expressing feline hexosaminidase produced enzymatic activity >75-fold normal at the brain injection site with little evidence of an immune infiltrate. Affected cats treated with feline-specific vectors by bilateral injection of the thalamus lived to 10.4 ± 3.7 months of age (n = 3), or 2.3 times as long as untreated cats. These studies support the therapeutic potential of AAV vectors for SD and underscore the importance of species-specific cDNAs for translational research.

Towards a vaccine to prevent cancer in Lynch syndrome patients

Germline mutations of DNA mismatch repair (MMR) genes predispose Lynch syndrome mutation carriers to the development of MMR-deficient tumors. MMR-deficient tumors show high-level microsatellite instability (MSI-H) and are typically characterized by a comparatively favorable prognosis and the absence of distant organ metastasis. Lynch syndrome-associated cancers are characterized by a pronounced local anti-tumoral immune response and usually display dense lymphocyte infiltration. This finding strongly suggested that the immune system may play an active role in the surveillance and biology of these cancers. The progression of MMR deficient cancers seems to be triggered by mutations in microsatellite sequences within gene-encoding regions. These mutations may cause shifts of the translational reading frame and thus give rise to the generation of potentially immunogenic frameshift peptides (FSP) at the carboxy terminal end of the respective gene products. FSP-specific immune responses are thought to represent one major mechanism by which the host's adaptive immune system can recognize and potentially control Lynch syndrome-associated MSI-H cancers. Consequently, vaccination with FSP antigens represent a promising approach for treatment of Lynch syndrome-associated cancers, potentially also suitable for tumor prevention in so far tumor-free Lynch syndrome germ line mutation carriers. This review will summarize the molecular mechanisms contributing to the immunological phenotype of MSI-H cancers. In addition, clinical perspectives will be discussed, focusing on MSI-H cancer-associated FSP antigens as potential targets for immune therapy approaches.

Multiplexed immunoassay to assess Shigella-specific antibody responses

Infection with Shigella spp. results in bacillary dysentery and a systemic and mucosal antibody response. The immune response is directed at multiple antigens, including LPS and the invasin plasmid antigen (Ipa) proteins, and is capable of conferring short-term, serotype-specific protection. Both live-attenuated and several subunit vaccine approaches have focused on inducing a pronounced mucosal immune response directed to the same antigens recognized after natural infection. Traditionally, Shigella-specific antibody responses are measured using ELISA. Although ELISAs are robust immunological assays, limited sample volume and assay costs often precludes its use for immunological evaluation against multiple antigens.To overcome these shortcomings, a novel assay has been developed to simultaneously measure specific antibody levels to six Shigella antigens, including three serotype-specific LPS preparations and three conserved protein antigens in a Luminex™-based system. Coupling methods were optimized to covalently link recombinant Ipa proteins (IpaB, IpaC, and IpaD) and purified LPS from Shigella sonnei, Shigella flexneri 2a, and Shigella dysenteriae 1 to unique bead sets.The antigen-coupled beads maintained stable reactivity with monoclonal antibodies (mAbs) for 6weeks (protein) to 3months (LPS). The specificity of the Luminex assay was similar to an ELISA, with the multiplexed assay providing a larger dynamic range. Comparable levels of antigen-specific reactivity were attained in monoplex or multiplex formats indicating limited interference. The correlations (R2) between the ELISA and the multiplexed assay along with the repeatability and reproducibility of the assay were very high. Minor changes in species-specific conjugated secondary antibodies allowed the optimized multiplexed assays to be used to assess antigen-specific antibodies in serum or blood eluted from filter paper isolated from mice and guinea pigs highlighting applicability of the assay for seroepidemiology and pre-clinical/clinical vaccine studies.

Association of HLA-DR7 with the Development of a Symptomatic Epstein-Barr Virus (EBV) Infection after Pediatric Renal Transplantation

Introduction: So far, it is unclear why some patients exhibit pronounced acute clinical EBV-related symptoms during post-transplant EBV primary infection, whilst others remain asymptomatic despite a high, persistent EBV viral load, over months or years. A genetic predisposition is likely. Methods: In the framework of a prospective, multicenter trial among 106 pediatric kidney allograft recipients (aged 11.1 ± 5.9 years), we therefore analyzed the prevalence of HLA class I and II alleles and a potential association of HLA alleles with the development of a symptomatic EBV infection (flu-like symptoms or infectious mononucleosis (IM)) in the first year post-transplant. Results: Patients expressing HLA-DR7 bore a significantly increased risk of developing a symptomatic EBV infection (univariate regression analysis: OR 4.77; 95%-CI 1.60-14.2; p=0.005; multivariate analysis: Fig. 1). The prevalence of the HLA-DR7 allele amounted to 25%. Having a comparable EBV risk constellation, HLA-DR7-positive patients suffered significantly more often (9/26 (35%)) a symptomatic EBV infection than HLA-DR7-negative recipients (8/80 (10%); p=0.008). Asymptomatic patients with a high EBV viral load tended to express HLA-DR7 less frequently than symptomatic patients with a high EBV viral load (3/17 (18%) vs. 6/11 (55%), p=0.095).Figure: [EBV HLA]Conclusions: Pediatric renal transplant recipients expressing HLA-DR7 develop significantly more often a symptomatic EBV infection than HLA-DR7-negative patients, possibly as a consequence of a pronounced immune response which, in the long run, may protect against PTLD. Indeed, HLA-DR7 induces a T helper cell reaction through presentation of EBNA1 (1) and is known to be a protective factor against the development of PTLD (2).

Association of HLA-DR7 with the Development of a Symptomatic Epstein-Barr Virus (EBV) Infection after Pediatric Renal Transplantation

Introduction: So far, it is unclear why some patients exhibit pronounced acute clinical EBV-related symptoms during post-transplant EBV primary infection, whilst others remain asymptomatic despite a high, persistent EBV viral load, over months or years. A genetic predisposition is likely. Methods: In the framework of a prospective, multicenter trial among 106 pediatric kidney allograft recipients (aged 11.1 ± 5.9 years), we therefore analyzed the prevalence of HLA class I and II alleles and a potential association of HLA alleles with the development of a symptomatic EBV infection (flu-like symptoms or infectious mononucleosis (IM)) in the first year post-transplant. Results: Patients expressing HLA-DR7 bore a significantly increased risk of developing a symptomatic EBV infection (univariate regression analysis: OR 4.77; 95%-CI 1.60-14.2; p=0.005; multivariate analysis: Fig. 1). The prevalence of the HLA-DR7 allele amounted to 25%. Having a comparable EBV risk constellation, HLA-DR7-positive patients suffered significantly more often (9/26 (35%)) a symptomatic EBV infection than HLA-DR7-negative recipients (8/80 (10%); p=0.008). Asymptomatic patients with a high EBV viral load tended to express HLA-DR7 less frequently than symptomatic patients with a high EBV viral load (3/17 (18%) vs. 6/11 (55%), p=0.095).Figure: [EBV HLA]Conclusions: Pediatric renal transplant recipients expressing HLA-DR7 develop significantly more often a symptomatic EBV infection than HLA-DR7-negative patients, possibly as a consequence of a pronounced immune response which, in the long run, may protect against PTLD. Indeed, HLA-DR7 induces a T helper cell reaction through presentation of EBNA1(1) and is known to be a protective factor against the development of PTLD(2).

Porcine reproductive and respiratory syndrome virus induces pronounced immune modulatory responses at mucosal tissues in the parental vaccine strain VR2332 infected pigs

Porcine reproductive and respiratory syndrome (PRRS) is a chronic viral disease of pigs caused by PRRS virus (PRRSV). The PRRSV VR2332 is the prototype North American parental strain commonly used in the preparation of vaccines. Goal of this study was to understand missing information on VR2332 induced immune modulation at the lungs and lymphoid tissues, the sites of PRRSV replication. Pigs were infected intranasally and samples collected at post-infection day (PID) 15, 30, and 60. Microscopically, lungs had moderate interstitial pneumonia, and the virus was detected in all the tested tissues. Peak antibody response and the cytokine IFN-γ secretion were detected at PID 30, with increased TGF-β until PID 60. Population of CD8+, CD4+, and CD4+CD8+T cells, Natural killer (NK) cells, and γδ T cells in the lungs and lymphoid tissues were significantly modulated favoring PRRSV persistence. The NK cell-mediated cytotoxicity was significantly reduced in infected pigs. In addition, increased population of immunosuppressive T-regulatory cells (Tregs) and associated cytokines were also observed in VR2332 strain infected pigs.

Liver-kidney recipients with chronic viral hepatitis C treated with interferon-alpha

Antiviral therapy with interferon-alpha (IFN-alpha) and pegylated IFN-alpha (PEG-IFN-alpha) for chronic hepatitis C (HCV)-infected kidney recipients remains controversial. IFN-alpha is not recommended in most cases because it induces severe acute graft rejection. However, IFN-alpha, as PEG-IFN-alpha, is associated with a more pronounced immune response, and is well tolerated in HCV-infected liver recipients without causing graft rejection. In combined liver-kidney transplant (LKT) recipients, IFN-alpha has been occasionally used and appears to be well tolerated. All LKT recipients with a functioning kidney and liver having a HCV replication and who needed IFN-alpha therapy have been included in the study. The occurrence of liver and/or renal acute rejection as well as the HCV replication has been collected. A total of 12 LKT patients treated with PEG-IFN-alpha plus ribavirin have been studied. No acute rejection was observed. Renal function remained stable during and after discontinuing treatment, without any graft dysfunction. Two patients had a partial viral response and four had a sustained viral response. All patients, whatever their viral response, had decreased liver-enzyme levels. Response to PEG-IFN-alpha therapy was correlated with steroid dose and transaminase level when PEG-IFN-alpha was started. These data suggest that the combination therapy of PEG-IFN-alpha plus ribavirin did not have a higher risk of acute kidney-graft rejection after liver-kidney transplantation.

Short Term High Fat Diet Challenge Promotes Alternative Macrophage Polarization in Adipose Tissue via Natural Killer T Cells and Interleukin-4

Inflammation in adipose tissue plays an important role in the pathogenesis of obesity-associated complications. However, the detailed cellular events underlying the inflammatory changes at the onset of obesity have not been characterized. Here we show that an acute HFD challenge is unexpectedly associated with elevated alternative (M2) macrophage polarization in adipose tissue mediated by Natural Killer T (NKT) cells. Upon 4d HFD feeding, NKT cells are activated, promote M2 macrophage polarization and induce arginase 1 expression via interleukin (IL)-4 in adipose tissue, not in the liver. In NKT-deficient CD1d(-/-) mice, M2 macrophage polarization in adipose tissue is reduced while systemic glucose homeostasis and insulin tolerance are impaired upon 4d HFD challenge. Thus, our study demonstrate, for the first time to our knowledge, that acute HFD feeding is associated with remarkably pronounced and dynamic immune responses in adipose tissue, and adipose-resident NKT cells may link acute HFD feeding with inflammation.

CCR5Δ32 Genotype Leads to a Th2 Type Directed Immune Response in ESRD Patients

BackgroundIn patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5Δ32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5Δ32 on inflammatory processes. Animal studies have shown that CCR5 deficiency is associated with a more pronounced Th2 type immune response, suggesting that in human CCR5Δ32 carriers the immune response may be more Th2 type directed. So, in the present study we determined the Th1-Th2 type directed immune response in ESRD patients carrying and not carrying the CCR5Δ32 genetic variant after stimulation.Methodology/Principal FindingsWe tested this hypothesis by determining the levels of IFN-γ and IL-4 and the distribution of Th1, Th2 and Th17 directed circulating CD4+ and CD8+ T cells and regulatory T cells (Tregs) after stimulation in ESRD patients with (n = 10) and without (n = 9) the CCR5Δ32 genotype. The extracellular levels of IFN-γ and IL-4 did not differ between CCR5Δ32 carriers and non carriers. However, based on their intracellular cytokine profile the percentages IL-4 secreting CD4+ and CD8+ T cells carrying the CCR5Δ32 genotype were significantly increased (p = 0.02, respectively p = 0.02) compared to non carriers, indicating a more Th2 type directed response. Based on their intracellular cytokine profile the percentages IFN-γ and IL-17 secreting T cells did not differ between carriers and non-carriers nor did the percentage Tregs, indicating that the Th1, Th17 and T regulatory response was not affected by the CCR5Δ32 genotype.Conclusions/SignificanceThis first, functional human study shows a more pronounced Th2 type immune response in CCR5Δ32 carriers compared to non carriers. These differences may be involved in the previously observed protection from inflammation-associated mortality in ESRD patients carrying CCR5Δ32.

An integrated microfluidic platform for in situ cellular cytokine secretion immunophenotyping

Rapid, quantitative detection of cell-secreted biomarker proteins with a low sample volume holds great promise to advance cellular immunophenotyping techniques for personalized diagnosis and treatment of infectious diseases. Here we achieved such an assay with the THP-1 human acute moncytic leukemia cell line (a model for human monocyte) using a highly integrated microfluidic platform incorporating a no-wash bead-based chemiluminescence immunodetection scheme. Our microfluidic device allowed us to stimulate cells with lipopolysaccharide (LPS), which is an endotoxin causing septic shock due to severely pronounced immune response of the human body, under a well-controlled on-chip environment. Tumor necrosis factor-alpha (TNF-α) secreted from stimulated THP-1 cells was subsequently measured within the device with no flushing process required. Our study achieved high-sensitivity cellular immunophenotyping with 20-fold fewer cells than current cell-stimulation assay. The total assay time was also 7 times shorter than that of a conventional enzyme-linked immunosorbent assay (ELISA). Our strategy of monitoring immune cell functions in situ using a microfluidic platform could impact future medical treatments of acute infectious diseases and immune disorders by enabling a rapid, sample-efficient cellular immunophenotyping analysis.

The Human Transcriptome During Nontyphoid Salmonella and HIV Coinfection Reveals Attenuated NFκB-Mediated Inflammation and Persistent Cell Cycle Disruption

Background. Invasive nontyphoid Salmonella (iNTS) disease is common and severe in adults with human immunodeficiency virus (HIV) infection in Africa. We previously observed that ex vivo macrophages from HIV-infected subjects challenged with Salmonella Typhimurium exhibit dysregulated proinflammatory cytokine responses.Methods. We studied the transcriptional response in whole blood from HIV-positive patients during acute and convalescent iNTS disease compared to other invasive bacterial diseases, and to HIV-positive and -negative controls.Results. During iNTS disease, there was a remarkable lack of a coordinated inflammatory or innate immune signaling response. Few interferon γ (IFNγ)--induced genes or Toll-like receptor/transcription factor nuclear factor κB (TLR/NFκB) gene pathways were upregulated in expression. Ex vivo lipopolysacharide (LPS) or flagellin stimulation of whole blood, however, showed that convalescent iNTS subjects and controls were competent to mount prominent TLR/NFκB-associated patterns of mRNA expression. In contrast, HIV-positive patients with other invasive bacterial infections (Escherichia coli and Streptococcus pneumoniae) displayed a pronounced proinflammatory innate immune transcriptional response. There was also upregulated mRNA expression in cell cycle, DNA replication, translation and repair, and viral replication pathways during iNTS. These patterns persisted for up to 2 months into convalescence.Conclusions. Attenuation of NFκB-mediated inflammation and dysregulation of cell cycle and DNA-function gene pathway expression are key features of the interplay between iNTS and HIV.

Morphological features of inflammation in the lungs of Wistar rats AFFECTED Lipopolysaccharide UNDER GIPOANDROGENEMII

In the experiment, Wistar rats reproduced the model of inflammation in the lungs in gipoandrogenemii by the introduction of LPS after testectomy. According to morphological, morphometric and cytological studies in castrated rats after administration of LPS in the lungs of more pronounced immune and inflammatory response, as evidenced by increased numbers of neutrophils in mezhalveolyarnyh partitions, hyperplasia bronhoassotsiirovannoy lymphoid tissue, the reduction in the bronchoalveolar washing fluid in the rate of neutrophils.

DNA immunization with a plasmid carrying the gene of hepatitis C virus protein 5A (NS5A) induces an effective cellular immune response

In spite of extensive research, no effective vaccine against hepatitis C virus (HCV) has been developed so far. DNA immunization is a potent technique of vaccine design strongly promoting the cellular arm of immune response. The genes encoding nonstructural HCV proteins (NS2-NS5B) are promising candidates for vaccine development. NS5A is a protein involved in viral pathogenesis, in the induction of immune response, and probably in viral resistance to interferon treatment. The objective of this study was to construct a DNA vaccine encoding NS5A protein and evaluate its immunogenicity. A plasmid encoding a full-size NS5A protein was produced using the pcDNA3.1 (+) vector for eukaryotic expression system. The expression of the NS5A gene was confirmed by immunoperoxidase staining of the transfected eukaryotic cells with anti-NS5A monoclonal antibodies. Triple immunization of mice with the plasmid vaccine induced a pronounced cellular immune response against abroad spectrum of NSSA epitopes as assessed by T-cell proliferation andsecretion of antiviral cytokines IFN-gamma and IL-2. In in vitro T-cell stimulation experiments, NS5A-derived antigens were modeled by synthetic peptides, recombinant proteins of various genotypes, and phages carrying exposed NS5A peptides. A novel immunomodulator Immunomax showed high adjuvant activity in DNA immunization. The data obtained indicate that the suggested DNA construct has a strong potential in the development of the gene vaccines against hepatitis C.

Gemini nanoparticles as a co-delivery system for antigen – CpG oligodeoxynucleotide adjuvant combination

Enhancement of antigen-specific immune responses could be achieved by co-delivery of antigens and adjuvants. CpG oligodeoxynucleotides (unmethylated cytosine-guanine tandems in a specific sequence; ODNs) increase innate and antigen-specific immune responses. Effective co-delivery approaches of CpG ODNs and antigens to antigen-presenting cells are needed to achieve more potent antigen-specific immune responses. We evaluated both cellular and humoural immune responses triggered by hen egg lysozyme (HEL), a model antigen, and CpG ODNs formulated in gemini surfactant and dioleoyl phosphatidylcholine-based nanoparticles as an intradermal and topical co-delivery system in a murine animal model. Overall, intradermal injection of HEL/CpG nanoparticles induced a more pronounced Th1 immune response compared with the HEL and HEL/CpG topical formulations, as evidenced by the shift in the Th2 response triggered by the antigen alone to a mixed Th1/Th2 immune response and increased the presence of interferon-gamma (IFN-γ) secreting cells in the spleen. However, in case of topical administration, the nanoparticle formulation of HEL produced enhanced immune response and immunomodulation even without the incorporation of CpG. The HEL-specific immune response and Th1 bias demonstrated the advantage of co-delivery of HEL/CpG ODNs by gemini nanoparticles intradermally, whereas, the adjuvant effect of the nanoparticle delivery system itself was more significant after topical treatment.

Quorum sensing is necessary for the virulence of Pseudomonas aeruginosa during urinary tract infection

Quorum sensing is a signaling pathway used by bacteria to monitor their population density by detecting small diffusible molecules. To understand the role of quorum sensing in pathogenesis of urinary tract infections, wild type Pseudomonas aeruginosa, having both functional las and rhl quorum sensing systems, and its isogenic single and double mutants were used in a mouse model of ascending urinary tract infection. Mice were evaluated on the basis of bacteriological and histopathological examinations, detection of acyl homoserine lactone, and the pathologic index factors of renal and bladder tissue. Single as well as double mutant strains were able to reach renal tissue, but they were not able to multiply and cause tissue damage. Reduced rates of infection, mild histopathologic lesions, and decreased production of pathologic index factors like myeloperoxidase, malondialdehyde, and reactive nitrogen intermediates were found in these groups of mice as compared to mice infected with a standard strain (PAO1) possessing both functional sensing systems. Loss of any one of the quorum-sensing components significantly reduced the in vivo virulence of P. aeruginosa in this mouse model of ascending urinary tract infection. Our results suggests that quorum-sensing signals may act as virulence factors and are essential for P. aeruginosa multiplication and virulence during the course of urinary tract infection.

Potent Early Immune Response After Kidney Transplantation in Patients of the European Senior Transplant Program

The increasing age of organ donors and the transplantation of older recipients have become clinical practice. Age-adapted immunosuppressive protocols considering these changes are currently not established. This study analyzed the age-dependent immune response after human kidney transplantation. One hundred renal allograft recipients were prospectively evaluated from 2004 to 2005. Patients older than 65 years of the European Senior Program receiving kidneys from donors older than 65 years were compared with recipients younger than 65 years receiving kidneys from donors younger than 65 years. Age-dependent modifications of the immune response were evaluated before transplantation and 7 days and 6 months after grafting by flow cytometry analysis of lymphocyte surface markers in peripheral blood. The cytokine pattern was determined by Cytometric Bead Array, T-cell alloreactivity by enzyme-linked immunospot analysis. There were no differences between the groups regarding patient survival, graft survival, and function at 6 months after transplantation. Before transplantation, 7 days and 6 months thereafter recipients older than 65 years demonstrated significantly elevated numbers of memory T-cells while counts for naive T-cells were significantly reduced. Numbers of activated cytotoxic cells were elevated with increasing age before and 7 days after transplantation. T-cell alloreactivity was more pronounced in older recipients at all time points. Seven days after transplantation tumor necrosis factor-alpha (TNF-alpha) levels were significantly higher, whereas TNF-alpha and interleukin-10 (IL-10) concentrations were significantly reduced after 6 months in older recipients. Our data demonstrate an initially pronounced immune response in elderly recipients receiving grafts from elderly donors. This observation supports the concept of a donor and recipient age-adapted immunosuppression.

A Th2 type of immune response is associated with increased resistance to Haemonchus contortus in naturally infected Gulf Coast Native lambs

Haemonchus contortus is one of the major nematode parasites causing substantial economic losses in small ruminant farming worldwide. Recently, effectiveness of anthelmintic treatment has decreased due to an increasing problem of nematode populations that have developed resistance to anthelmintics. Efforts to develop effective vaccines have had limited success. There are certain breeds of sheep that are relatively resistant to the parasite including Gulf Coast Native (Native) sheep. Understanding the protective nature of the immune response that helps these breeds of sheep control infection could enable the development of vaccines to enhance control programs. This experiment was designed to compare the immunological responses of resistant Native versus susceptible Suffolk sheep in order to identify the mechanisms responsible for this resistance. Immune responses were evaluated in naturally infected Native and Suffolk lambs that grazed pasture contaminated predominantly with H. contortus. Ten lambs of each breed grazed together for 42 days. Fecal, blood and serum samples were collected on 0, 2, 4, 7, 10, 14, 21, 28, 35 and 42 days of exposure. Five lambs of each breed were necropsied on day 35 and five on day 42 for nematode recovery and abomasal tissue sample collection. Throughout the course of infection, Native lambs had significantly lower FEC, significantly lower PCV reduction percent, and significantly higher serum IgE after day 14 and increased expression of IL-4 on day 10 post-exposure compared to Suffolk lambs. At both necropsy time points, Native lambs had significantly greater numbers of mucosal mast cells, eosinophils and globule leukocytes in abomasal mucosa than Suffolk lambs. Results indicated that Native lambs had a more pronounced immune response to infection with H. contortus than Suffolk lambs which may be responsible for the observed resistance to infection.

Molekulare Pathogenese

Colorectal cancer has the second highest mortality of all cancers in Germany. In spite of advances in surgical and chemotherapeutic treatment, efficient new therapies need to be developed. In recent years, advances have been achieved by novel targeted therapies that are specifically directed against altered signaling pathways of malignant cells. Colorectal cancers represent a heterogeneous tumor entity, and response to targeted therapies varies individually. About 15% of colorectal carcinomas are characterized by a deficient DNA mismatch repair system and microsatellite instability (MSI). These MSI cancers apparently have a decreased sensitivity to chemotherapy and frequently show evidence of a pronounced anti-tumoral immune response of the host. This immune response is likely to be mediated by a high number of tumor-specific antigens generated during MSI tumorigenesis. Interventions specifically targeting these antigens may be the basis for novel therapeutic strategies in MSI colorectal cancer and will be evaluated in clinical trials.