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PubMed1997

Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization.

Recent advances in our understanding of the immune response are allowing for the logical design of new approaches to cancer immunization. One area of interest is the development of new immune adjuvants. Immunostimulatory oligodeoxynucleotides containing the CpG motif (CpG ODN) can induce production of a wide variety of cytokines and activate B cells, monocytes, dendritic cells, and NK cells. Using the 38C13 B cell lymphoma model, we assessed whether CpG ODN can function as immune adjuvants in tumor antigen immunization. The idiotype served as the tumor antigen. Select CpG ODN were as effective as complete Freund's adjuvant at inducing an antigen-specific antibody response but were associated with less toxicity. These CpG ODN induced a higher titer of antigen-specific IgG2a than did complete Freund's adjuvant, suggesting an enhanced TH1 response. Mice immunized with CpG ODN as an adjuvant were protected from tumor challenge to a degree similar to that seen in mice immunized with complete Freund's adjuvant. We conclude that CpG ODN are effective as immune adjuvants and are attractive as part of a tumor immunization strategy.

Adjuvants, Immunologic↗

PubMedDate not supplied

Immune response, not immune maintenance, is energetically costly in wild white-footed mice (Peromyscus leucopus).

Understanding the cost of immune function is essential for more accurate characterization of energy budgets of animals and better understanding of the role of immunity in the evolution of life-history strategies. We examined the energetic cost of maintaining a normally functioning immune system and mounting a mild immune response in wild male white-footed mice (Peromyscus leucopus). To evaluate the cost of maintaining immunocompetence, we compared resting and daily metabolic rates (RMR; DMR) and masses of body organs of mice whose immune systems were suppressed by cyclophosphamide with those of control mice. To evaluate the cost of mounting an immune response, we measured RMR, DMR, and organ masses in mice whose humoral and cell-mediated immune responses had been stimulated by injections of sheep red blood cells and phytohemagglutinin, respectively. Immunosuppression resulted in a significant reduction in circulating leukocytes, by 225%, but no significant effect on metabolic rates or organ masses. Immunochallenged animals showed no significant differences in metabolic rates compared with control animals but did exhibit significantly smaller dry masses of the small intestine and testes, by 74% and 22%, respectively. We concluded that the cost of maintaining the immune system was minimal. In contrast, there was a significant energetic cost of mounting an immune response that, depending on its magnitude, can be met through reductions in energy allocation to other physiological systems.

Animals↗

PubMed1997

Intranasal immunization is superior to vaginal, gastric, or rectal immunization for the induction of systemic and mucosal anti-HIV antibody responses.

Vaginal anti-HIV antibody responses may be beneficial, and possibly required, for vaccine-induced protection against HIV infection acquired through receptive vaginal intercourse. We have previously determined that intranasal immunization with a hybrid HIV peptide and cholera toxin induced vaginal anti-HIV IgA responses in BALB/c and C57BL/6 mice. To determine if vaginal, gastric, or rectal boosting would enhance the induction of vaginal anti-HIV IgA responses over those observed with intranasal immunization only, C57BL/6 mice were intranasally immunized with the hybrid HIV peptide T1SP10MN(A) and cholera toxin (days 0 and 14) and boosted via the vaginal, gastric, or rectal route (days 7 and 28). Four intranasal immunizations was superior to all other immunizations evaluated for the induction of plasma anti-peptide IgG, vaginal anti-peptide IgG and IgA, and peptide-specific delayed-type hypersensitivity. In addition, intranasal priming with gastric boosting was associated with greatly elevated total serum IgE concentrations whereas intranasal immunization only was associated with only a modest increase in total serum IgE. These results suggest that intranasal immunization is a viable route of immunization for the induction of systemic and mucosal anti-HIV immune responses.

AIDS Vaccines↗

PubMed2000

Murine xenogeneic immune responses to the human testis: a presumed immune-privileged tissue.

INTRODUCTION: Immune privilege provides a natural paradigm for potentially down-regulating allogeneic and xenogeneic inflammatory immune responses. Fas ligand has been suggested as a general underlying mechanism of immune privilege; the human Fas ligand has been shown to ligate murine Fas in vitro. METHODS: In this study, we examined whether the human testicular xenograft, a presumed immune-privileged tissue would have prolonged survival in mice. In addition, in vitro and in vivo murine xenogeneic immune responses to the human testicular xenografts were characterized using MHC class I, MHC class II, CD4, CD8, CD4/8 knockout mice. RESULTS: Unlike in rodent testis, Fas ligand mRNA is not expressed and Fas is highly expressed in human testis. Human testicular xenografts are immunogenic, and do not induce any preferential pattern of recipient systemic Th1 or Th2 cytokine bias. Interestingly, an indefinite survival of the human testicular xenografts is observed in murine MHC class II knockout mice, whereas the human skin xenografts were rejected without a delay. In vivo murine immune responses to human testicular xenografts require a recipient MHC class II-dependent CD4 T cell-mediated process that appears to depend on B7-1/B7-2 costimulatory signals. CONCLUSIONS: Our results demonstrate that the concept of immune privilege, as defined by the expression of Fas ligand and prolonged survival after transplantation, cannot be extended to human testis. The stringent restriction of murine xenogeneic immune responses to discordant human testicular xenografts to the indirect MHC class II-dependent CD4 T cell-mediated pathway suggests a potential venue for immune modulation to induce tolerance across a discordant species barrier.

Animals↗

PubMed1993

Association of the lactococcin A immunity factor with the cell membrane: purification and characterization of the immunity factor.

The physicochemical characteristics of the lactococcin A immunity protein, as deduced from its gene sequence, were used to devise a procedure for its purification. The protein was purified from cell extracts by cation-exchange and reverse-phase chromatography. As judged from the amino acid composition and amino acid sequencing, the immunity protein is not post-translationally processed by cleavage at its N- or C-terminus. Consequently, the absorption coefficient at 280 nm, the isoelectric point, and the molecular mass of the immunity protein may be calculated to be, respectively, 8.2 x 10(3) M-1 cm-1, 10.2 and 11,163 Da from the amino acid sequence predicted from the nucleotide sequence. The immunity protein is a major cell protein component--one cell may contain (to an order of magnitude) 10(5) molecules--and it is in part associated with the cell membrane, as judged by immunoblot analysis of membrane vesicle-associated proteins. Exposing lactococcin-A-sensitive cells to an excess of the immunity protein did not affect the lactococcin-A-induced killing of the cells, indicating that the immunity protein does not protect cells by simply binding to lactococcin A, nor to externally exposed domains on the cell surface. Exposing immune-positive cells to antiserum against the immune protein did not sensitize the cells to lactococcin A, suggesting that the immunity protein in fact does not act extracellularly.

Amino Acid Sequence↗

PubMed1985

Monoclonal antibodies against complement 3 neoantigens for detection of immune complexes and complement activation. Relationship between immune complex levels, state of C3, and numbers of receptors for C3b.

C3-bearing immune complexes and C3 activation products were detected by using two monoclonal antibodies, one specific for a neoantigenic determinant on C3c and the other for C3d. To quantitate immune complexes, the anti-C3c or anti-C3d antibodies were fixed to microtiter plates and reacted with test plasma. The binding of C3-bearing immune complexes in this plasma was then measured with radioisotope- or enzyme-labeled anti-human IgG. To test for C3 breakdown products, solid-phase monoclonal antibody to the C3d neoantigen was reacted with EDTA-plasma samples, and fixed iC3b or C3d was measured with a polyclonal anti-C3 antibody. Patients with autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren's syndrome, and paracoccidioidomycosis were found to contain immune complexes bearing C3b/iC3b or C3d. In most conditions, there were more C3d-containing immune complexes than C3b/iC3b. Although CR1 (C3b receptors) rapidly converted immune complex-bound iC3b to C3dg/C3d and lupus patients had reduced CR1, no correlation between the state of C3 on circulating immune complexes or levels of immune complexes and CR1 numbers was seen. However, levels of C3-fixing ICs correlated with levels of C3 activation products. This assay system with monoclonal antibodies to neoantigens expressed on activated, but not native, C3 provides sensitive and specific means for detecting and classifying C3-fixing immune complexes and for assessing C3 activation.

Antibodies, Monoclonal↗

PubMed2004

Reduction of beta-endorphin-containing immune cells in inflamed paw tissue corresponds with a reduction in immune-derived antinociception: reversible by donor activated lymphocytes.

UNLABELLED: The functional integrity of the immune system is essential for peripheral antinociception. Previous studies have demonstrated that immune cells elicit potent antinociception in inflamed tissues and that corticotropin-releasing factor-induced antinociception is significantly inhibited in animals that have undergone cyclosporin A (CsA)-induced immunosuppression. In this study, we examined the effect of a single bolus of CsA on inflammatory nociception. CsA-treated rats had substantially increased nociception compared with nonimmunosuppressed rats, consistent with a reduction in circulating and infiltrating lymphocytes. Furthermore, CsA-treated rats had inhibition of corticotropin-releasing factor-induced immune-derived antinociception, which was dose-dependently reversed by IV injection of concanavalin A-activated donor lymphocytes (1.0-7.0 x 10(6) cells/0.1 mL). In conclusion, our findings provided further evidence that opioid-containing immune cells are essential for peripheral analgesia. It is evident from these findings that control of inflammatory pain relies heavily on a functioning immune system. IMPLICATIONS: The immune system not only contributes to inflammation, but also provides localized analgesia. A depleted immune system results in a reduction of immune-derived analgesia and a potentiation of inflammatory pain. Donor activated lymphocytes reverse these effects, highlighting the importance of a functional immune system in inflammatory pain.

Analgesia↗

PubMed2025

Tumor-immune partitioning and clustering algorithm for identifying tumor-immune cell spatial interaction signatures within the tumor microenvironment.

BACKGROUND: Growing evidence supports the importance of characterizing the organizational patterns of various cellular constituents in the tumor microenvironment in precision oncology. Most existing data on immune cell infiltrates in tumors, which are based on immune cell counts or nearest neighbor-type analyses, have failed to fully capture the cellular organization and heterogeneity. METHODS: We introduce a computational algorithm, termed Tumor-Immune Partitioning and Clustering (TIPC), that jointly measures immune cell partitioning between tumor epithelial and stromal areas and immune cell clustering versus dispersion. As proof-of-principle, we applied TIPC to a prospective cohort incident tumor biobank containing 931 colorectal carcinoma cases. TIPC identified tumor subtypes with unique spatial patterns between tumor cells and T lymphocytes linked to certain molecular pathologic and prognostic features. T lymphocyte identification and phenotyping were achieved using multiplexed (multispectral) immunofluorescence. In a separate hepatocellular carcinoma cohort, we replaced the stromal component with specific immune cell types-CXCR3+CD68+ or CD8+-to profile their spatial relationships with CXCL9+CD68+ cells. RESULTS: Six unsupervised TIPC subtypes based on T lymphocyte distribution patterns were identified, comprising two cold and four hot subtypes. Three of the four hot subtypes were associated with significantly longer colorectal cancer (CRC)-specific survival compared to a reference cold subtype. Our analysis showed that variations in T-cell densities among the TIPC subtypes did not strictly correlate with prognostic benefits, underscoring the prognostic significance of immune cell spatial patterns. Additionally, TIPC revealed two spatially distinct and cell density-specific subtypes among microsatellite instability-high colorectal cancers, indicating its potential to upgrade tumor subtyping. TIPC was also applied to additional immune cell types, eosinophils and neutrophils, identified using morphology and supervised machine learning; here two tumor subtypes with similarly low densities, namely 'cold, tumor-rich' and 'cold, stroma-rich', exhibited differential prognostic associations. Lastly, we validated our methods and results using The Cancer Genome Atlas colon and rectal adenocarcinoma data (n = 570). Moreover, applying TIPC to hepatocellular carcinoma cases (n = 27) highlighted critical cell interactions like CXCL9-CXCR3 and CXCL9-CD8. CONCLUSIONS: Unsupervised discoveries of microgeometric tissue organizational patterns and novel tumor subtypes using the TIPC algorithm can deepen our understanding of the tumor immune microenvironment and likely inform precision cancer immunotherapy.

Humans↗

PubMed2005

[Study on the direct MAIPA technique in the differential diagnosis of immune and non-immune thrombocytopenia].

OBJECTIVE: To evaluate the clinical usefulness of direct monoclonal antibody immobilization of platelet antigen (MAIPA) technique in the differential diagnosis of immune and non-immune thrombocytopenia. METHODS: Platelet-bound autoantibodies in thrombocytopenic patients (immune and non-immune) were measured by direct MAIPA. Monoclonal antibodies against GP II b/III a, GPIb and GP I a/II a were used. RESULTS: The positive rates of platelet-bound GP-specific autoantibodies between immune (76.4%) and non-immune thrombocytopenia (3.6%) were significantly different (P < 0.05). The direct MAIPA had a sensitivity of 76.4%, a specificity of 96.4%, and a positive predictive value of 97.1% for the diagnosis of immune thrombocytopenia. There was a significant inverse correlation between platelet-bound GP II b/III a specific autoantibody levels and platelet counts (r = -0.338, P < 0.05). CONCLUSION: The direct MAIPA technique can be used to differentiate immune from non-immune thrombocytopenias.

Adolescent↗

PubMed1991

Update on adult immunization. Recommendations of the Immunization Practices Advisory Committee (ACIP).

This statement on adult immunization is a supplement to the "General Recommendations on Immunization" of the Immunization Practices Advisory Committee (ACIP) (1) and updates the previous supplement published in September 1984. This statement presents an overview on immunization for adults and makes specific immunization recommendations. The statement provides information on vaccine-preventable diseases; indications for use of vaccines, toxoids, and immune globulins recommended for adults; and specific side effects, adverse reactions, precautions, and contraindications associated with use of these immunobiologics. It also gives immunization recommendations for adults in specific age groups and for those who have special immunization requirements because of occupation, life-style, travel, environmental situations, and health status. This statement is a compendium of ACIP recommendations and will not be updated regularly. The ACIP periodically reviews individual immunization statements that are published in the MMWR. The reader must use the detailed, up-to-date individual statements in conjunction with this compendium to keep abreast of current information. A list of the current ACIP recommendations for specific diseases and vaccines can be found in Appendix 1.

Adolescent↗

PubMed1972

Studies on heterologous immunity in schistosomiasis. 6. Observations on cross-immunity to Ornithobilharzia turkestanicum, Schistosoma bovis, S. mansoni, and S. haematobium in mice, sheep, and cattle in Iran.

Experiments were carried out in mice, cattle, and sheep to investigate the possibility that heterologous immune reactions may occur between the schistosomes prevalent in man and domestic animals in Iran. Immunization with Ornithobilharzia turkestanicum from cattle produced a considerable degree of immunity in mice against challenge with Schistosoma bovis, S. haematobium, and S. mansoni. The results of immunizing cattle with O. turkestanicum, S. bovis, and S. haematobium were even more striking; there was a reduction of 30-40% in the number of adult worms and a proportionally greater reduction in the tissue egg counts. Sheep developed a less marked immunity. Supplementary experiments on homologous immunity showed that mice developed a considerable degree of immunity against S. bovis. The results of the heterologous immunity experiments with S. haematobium and S. bovis are of particular interest as both parasites often occur in the same area and are often transmitted by the same snail host, man and cattle being exposed to the cercariae of both species simultaneously. The reciprocal immunity produced by these infections may be mutually beneficial in limiting the severity of schistosomiasis in man and domestic animals in the endemic areas.

Animals↗

PubMed1983

Influence of immune complex lattice on the C1q solid phase assay as determined with covalently cross-linked immune complexes.

The influence of the lattice of immune complexes on the C1q solid phase assay was examined using covalently cross-linked 125I-labelled immune complexes, separated into pools of varying and stable lattice. The C1q binding of antibodies alone, of Ag1Ab1, and of Ag2Ab2 could not be distinguished from each other statistically; but with increasing, higher lattices, immune complexes bound more efficiently to C1q. The binding of these immune complexes to C1q was also measured with 131I-labelled antibodies to IgG in the immune complexes. The detection of bound immune complexes by this indirect method showed the same order of binding efficiency as that observed by the direct measurement of immune complex binding. Up to a critical level, the binding of 131I-antibodies to IgG was proportional to the 125I-IgG in the bound complexes, and was independent of the lattice of complexes. This proportionality, however, was lost at higher levels of binding. The presence of serum diminished the binding of both large latticed and small latticed immune complexes, but serum did not alter the order of binding efficiency and the order of detection of binding using 131I-antibodies to IgG. The conclusion was reached that no single ideal standard for this assay can be currently designed to permit accurate quantitation of the concentration of immune complexes of varying lattice.

Antigen-Antibody Complex↗

PubMedDate not supplied

Studies on Pasteurella multocida. VI. Nature of systemic immunity and analysis of the correlation between levels of immunity induced by various fowl cholera vaccines and protection against challenge.

The nature of the systemic immunity induced by various vaccines against fowl cholera disease in turkeys was investigated. Used as vaccines were three avirulent strains (CU, M2283, and P1580) of Pasteurella multocida administered in the drinking water and a bacterin administered parenterally. A passive hemagglutination test was developed to measure levels of systemic humoral immunity. Systemic cell-mediated immune response was assayed by an in vitro immunostimulation microculture system utilizing peripheral blood lymphocytes. The bacterin induced high levels of systemic humoral and cell-mediated immune responses which respectively persisted for 8 and 6 weeks. The CU strain of live vaccine induced average levels of systemic immunity (humoral and cell-mediated) which respectively persisted for 4 and 6 weeks. The M2283 strain of live vaccine also induced average levels of systemic immunity (less than induced by the CU strain) which respectively persisted for 4 and 6 weeks. The P1580 strain of live vaccine induced low levels of systemic immunity which persisted for only 2 weeks. Results from data generated from an analysis of correlation between levels of immunity and protection indicate that systemic immunity (humoral and cell-mediated) played a significant role.

Administration, Oral↗

PubMed1995

Protective immunity to Pasteurella multocida heat-labile toxin by intranasal immunization in rabbits.

Heat-labile Pasteurella multocida toxin (PMT) is an important virulence factor of some isolates from rabbits. To determine whether protective immunity to PMT could be induced in rabbits by intranasal immunization with heat-inactivated PMT, we immunized groups of rabbits intranasally at days 0, 7, 14, and 21 with inactivated PMT, with or without cholera toxin, an adjuvant for the mucosal immune system. Significant increases in anti-PMT IgA in nasal lavage samples and anti-PMT serum IgG, as determined by enzyme-linked immunosorbent assay, developed within 2 weeks after initial immunization. Coadministration of cholera toxin with inactivated PMT enhanced anti-PMT activity in the samples. Rabbits similarly immunized on days 0, 7, and 14 were challenged with PMT, and tissues were graded histologically on a numeric scale of lesion severity. Immunization conferred partial protection against development of pneumonia, pleuritis, hepatic necrosis, and testicular atrophy in rabbits challenged 16 days after initial immunization. Thus, immunization with inactivated PMT stimulates a protective response to PMT challenge in rabbits that is enhanced by coadministration of cholera toxin.

Administration, Intranasal↗

PubMed1996

Study on specific mucosal immunity by intranasal immunization of outer membrane protein P6 of Haemophilus influenzae with cholera toxin B subunit.

Effective induction of the specific mucosal immunity against the outer membrane protein P6 of Haemophilus influenzae was investigated. Twenty-four BALB/c mice were intranasally immunized with P6, twice, with 2 weeks in between, with or without intranasal cytokine treatment. The intranasal immunization evoked both anti-P6 specific mucosal IgA immunity and systemic IgG immunity. In addition, intranasal administration of rIL-2 and rIL-5 enhanced anti-P6 specific immune response was maintained for 3 weeks after the final immunization with the intranasal cytokine treatment. These suggest the possibility of intranasal immunization and the advantage of intranasal administration of cytokines for eliciting both mucosal and systemic immunity.

Administration, Intranasal↗

PubMed1993

Passive-active immunization in infants of hepatitis Be antigen-positive mothers. Comparison of the efficacy of early and delayed active immunization.

OBJECTIVE: To assess the efficacy of late active immunization against hepatitis B concomitant with diphtheria, pertussis, tetanus, and polio vaccine in high-risk infants receiving hepatitis B immune globulin at birth. DESIGN: Randomized study of infants born to mothers positive for hepatitis B surface antigen (HBsAg) and hepatitis Be antigen (HBeAg). SETTING: Three large city hospitals and one rural area providing prenatal care and obstetric services. SUBJECTS: Eighty neonates of HBsAg- and HBeAg-positive carrier mothers received 0.5 mL/kg of body weight hepatitis B immune globulin within 2 hours of birth and hepatitis B vaccine (10 micrograms) at 0, 1, 2, and 11 months of age (group A) or at 3, 4, 5, and 11 months of age concomitant with diphtheria, pertussis, tetanus, and polio immunization (group B). A second dose of hepatitis B immune globulin was given to infants on schedule B at 3 months. MAIN OUTCOME MEASURES: Blood samples were collected at 0, 3, 6, 11, and 12 months of age and tested for antibodies against hepatitis B core antigen and HBsAg. Follow-up visits were scheduled annually up to 5 years of age. RESULTS: Eight infants were excluded from analysis. During the study period, six children became HBsAg carriers, three in each group, which corresponds to a 5-year incidence of infection of 9% and 8% for groups A (three of 35) and B (three of 37), respectively. Subclinical infections (persistent anti-HBc positivity beyond month 12 or appearance of anti-HBc) were encountered in another eight infants (four in each group). CONCLUSION: Late active immunization starting at 3 months of age appears to provide similar protective efficacy as active immunization starting at birth when combined with hepatitis B immune globulin at 0 and 3 months of age.

Adult↗

PubMed1984

Chronic immune stimulation by sperm alloantigens. Support for the hypothesis that spermatozoa induce immune dysregulation in homosexual males.

Putative, sperm-induced allogeneic immunization was correlated with immune dysregulation in a study of 30 asymptomatic, monogamously paired homosexual males. Evidence for allogeneic immunization existed among 19 of 26 homosexual males who were anal sperm recipients. No evidence for any form of alloimmunization was found in four exclusive sperm donors. Immune dysregulation in the form of a reduced effector/suppressor T-cell ratio (Te/Ts less than 1.0) was exclusively documented in eight anal-sperm-recipient homosexual males, five of whom also manifested evidence for allogeneic immunization. In three of those, immune dysregulation was further manifested by functional T-cell deficiency in the form of a subnormal (less than 50 cu mm) local graft-v-host reaction. Similar evidence for alloimmunization was associated with a reduced Te/Ts ratio (0.85) in the female of a heterosexual couple who routinely practiced anal intercourse. Based on these findings, we suggest that chronic, repeated exposure to sperm during anal intercourse results in a high frequency of allogeneic immunization and may play an important role in the development of acquired immune dysregulation among homosexual males.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Lack of antigen-specific immune responses in anti-IL-7 receptor alpha chain antibody-treated Peyer's patch-null mice following intestinal immunization with microencapsulated antigen.

Peyer's patches (PP) represent a well-characterized inductive site in gut-associated lymphoid tissue that actively acquires antigens from the intestinal lumen. It was reported that organized PP are not required for antigen-specific IgA responses induced by oral immunization with soluble antigen mixed with the mucosal adjuvant, cholera toxin. However, the role of PP in the induction of mucosal and systemic immune responses remains to be clarified in the case of particulate antigen. Here, we created PP-null mice by treating them with monoclonal anti-IL-7 receptor alpha chain (IL-7 R alpha) antibody during gestation and then immunized with antigen-encapsulated poly-lactic acid (PLA) microspheres. Brisk OVA-specific antibody responses were noted in serum and fecal extracts of normal mice following direct intestinal immunization with OVA in PBS (OVA-PBS) as well as in PLA-microspheres (OVA-MS). Antibody production was similarly elevated in PP-null mice immunized with OVA-PBS via direct injection into the intestinal tract. In contrast, OVA-specific antibody responses were dramatically decreased in both serum and fecal extracts collected from PP-null mice immunized intestinally with OVA-MS. These results were further supported by the number of OVA-specific antibody-forming cells detected in the spleen and intestinal lamina propria. PP deficiency also resulted in the reduction in OVA-specific Th1/Th2 cell responses in the spleen and mesenteric lymph nodes of mice intestinally immunized with OVA-MS. These results suggested that organized PP do, in fact, play a crucial role in the induction of antigen-specific immune responses against ingested particulate antigen.

Animals↗