scholarly journals Genetic control of immune response. The dose of antigen given in aqueous solution is critical in determining which mouse strain is high responder to poly(LTyr, LGlu)-poly(LPro)--poly(LLys).

1975 ◽  
Vol 141 (5) ◽  
pp. 1057-1072 ◽  
Author(s):  
S Jormalainen ◽  
E Mozes ◽  
M Sela
Keyword(s):  
Aqueous Solution ◽  
Serum Antibody ◽  
Optimal Dose ◽  
Primary Response ◽  
High Responder ◽  
Secondary Response ◽  
Similar Proportion ◽  
Major Histocompatibility Locus ◽  
Low Responder ◽  
Higher Doses

Antibody response to different doses of (T,G)-Pro--L, given in aqueous solution, was investigated in the high responder SJL and low responder DBA/1 strains by measuring hemolytic plaque-forming cells (PFC) in the spleens as well as hemagglutination titers in the sera. The gene responsible for the difference between the two strains in the response to this antigen, given in complete Freund's adjuvant, has been previously denoted Ir-3. This gene is not linked to the major histocompatibility locus. In the response to the optimal dose (1 mug) of antigen, no difference could be shown between the strains. The peak of the response and the numbers of direct and indirect PFC were similar in both strains in the primary and secondary response. After injection of higher doses (10-100 mug) of antigen, both the direct and indirect PFC responses were lower in the low responder than in the high responder strain. Moreover, the peak of the response occurred earlier in the high responder strain in the primary response to the 10 mu dose of antigen. After administration of a suboptimal dose (0.02 mug) of antigen, the low responder strain produced in the primary response 4-20 times more indirect plaques than the high responder strain. Also the number of direct plaques was higher in the low responder than in the high responder strain. The serum antibody responses to the optimal and higher doses of antigen were parallel to the PFC responses. From inhibition of PFC with free antigen, it was concluded that a similar proportion of cells was producing high and low affinity antibodies to (T,G)-Pro--L in both strains. High and low zone tolerance could be induced in the two strains with (T,G)-Pro--L, but no difference could be shown between the strains. It is suggested that the Ir-3 gene plays a role in the regulation of the balance stimulation and suppression according to the dose of antigen given.

scholarly journals Effect of colchicine on the antibody response. I. Enhancement of antibody formation in mice.

1978 ◽  
Vol 147 (4) ◽  
pp. 1213-1227 ◽  
Author(s):  
P N Shek ◽  
A H Coons
Keyword(s):  
Antibody Response ◽  
Antibody Formation ◽  
Suppressor Cells ◽  
Optimal Dose ◽  
Primary Response ◽  
Secondary Response ◽  
Structural Isomer ◽  
Protein Antigens ◽  
Critical Timing ◽  
Circulating Antibody

Colchicine (CC) enhances the antibody response in mice to protein antigens, like diphtheria toxoid and human gamma globulin, as well as to the 2,4,6-trinitrophenyl hapten. Maximal enhancement was observed when CC was administered to animals on the same day as the injection of antigen. The optimal dose of CC was in the range of 1.0-1.5 mg/kg body weight. The enhanced antibody formation was evident from elevated circulating antibody titers and from an increased number of antibody plaque-forming cells (PFC) of the spleen. The circulating antibody titer of CC-treated animals was higher than that of control animals by a factor of about 3-7 in the primary response, and by a factor of at least 15 in the secondary response. In terms of the number of antibody forming cells, CC enhanced the primary PFC response by approximately equal to 100%, and the secondary PFC response by as high as fivefold. The enhancing effect of CC seemed to be related to its mitosis-blocking capacity since (a) vinblastine another antimitotic drug, was found to be as effective as CC and (b) lumicolchicine, the non-anti-mitotic structural isomer of CC, was ineffective in potentiating antibody responses. The critical timing in the administration of CC on the same day as antigen suggests that most likely, the mitotic poison was acting on antigen-stimulated early dividing suppressor cells.

scholarly journals Immunization with antigen and interleukin 2 in vivo overcomes Ir gene low responsiveness.

1985 ◽  
Vol 162 (1) ◽  
pp. 381-386 ◽  
Author(s):  
H Kawamura ◽  
S A Rosenberg ◽  
J A Berzofsky
Keyword(s):  
Specific Antibody ◽  
Time Course ◽  
Recombinant Dna ◽  
Interleukin 2 ◽  
Serum Antibody ◽  
Fold Increase ◽  
High Responder ◽  
Local Concentration ◽  
Low Responder

We studied the effect of purified interleukin 2 (IL-2), made by recombinant DNA techniques, on the serum antibody response to myoglobin in high- and low-responder mice. Previous studies (6, 7) have shown that this response is controlled by H-2-linked Ir genes. The IL-2 was emulsified with the antigen in complete Freund's adjuvant to provide a sustained high local concentration. In low-responder B10.BR mice, a single dose (optimum 50,000 U) resulted in a consistent 10-50-fold increase in specific serum antibody throughout the time course of the response, from 10 d to 46 d after immunization. In contrast, no effect of IL-2 was seen in congenic high-responder B10.D2 mice. With IL-2, the low-responder mice achieved specific antibody levels comparable to those of high responders. Vehicle alone had no effect, and IL-2 alone, without antigen, did not induce myoglobin-specific antibody. No effect of IL-2 was seen in athymic nude mice of high-responder H-2 haplotype. The effect of IL-2 may be on a small number of responding T cells in the low responder mice, but it is possible that IL-2 also acts directly on B cells in a response that remains T-dependent, and therefore is not observed in athymic mice. We suggest that IL-2 may enhance suboptimal T cell help in the low responder, whereas help is not limiting in the high responder. This approach may enable the study of antibody responses in low responders otherwise too weak to analyze, and may be useful in producing antibodies to poorly immunogenic antigens. Potential clinical uses include immunization with weak antigens in normal patients, or with any antigen in certain immunodeficient patients.

scholarly journals CYTODYNAMICS OF THE IMMUNE RESPONSE IN TWO LINES OF MICE GENETICALLY SELECTED FOR "HIGH" AND "LOW" ANTIBODY SYNTHESIS

1972 ◽  
Vol 135 (5) ◽  
pp. 1071-1094 ◽  
Author(s):  
G. Biozzi ◽  
C. Stiffel ◽  
D. Mouton ◽  
Y. Bouthillier ◽  
C. Decreusefond
Keyword(s):  
Immune Response ◽  
Cellular Response ◽  
Doubling Time ◽  
Selective Breeding ◽  
Plasma Cells ◽  
Serum Antibody ◽  
Optimal Dose ◽  
Target Cells ◽  
Blast Cells ◽  
Low Responder

Two lines of mice have been separated by selective breeding for the character "agglutinin production to heterologous erythrocytes." Around the 18th generation of selection the two lines could be considered as homozygous for the character investigated. This trait is under the control of a group of additive genes. The interline difference in the production of anti-SE agglutinins was verified for the range of antigen doses from subimmunogenic to maximal. After intravenous immunization with an optimal dose of SE, the duration of the exponential rise in serum antibody was 4–5 days in both lines. At this time most of the interline difference in responsiveness is already expressed. A cytodynamic study carried out in terms of plaque-forming cells (PFC) and rosette-forming cells (RFC) in the spleen during the exponential phase showed that the principal interline difference is found in the doubling time of cells engaged in the immune response. More precise cytodynamic analysis made in terms of RFC showed that the doubling time of RFC is 9 hr in high responder and 16 hr in low responder mice. The duration of the exponential rise and the number of target cells stimulated by antigen is the same in both lines. The interline difference at the end of the exponential rise (4 days postimmunization) is larger in terms of serum antibody (30–40-fold) than in terms of PFC or RFC (20- and 11-fold, respectively). A morphological study of RFC in nonimmunized mice showed that about 90% of rosettes were formed by small lymphocytes in both lines. The remainder were medium-sized lymphocytes. At the peak of the cellular response the RFC have differentiated into large lymphocytes, blast cells, and plasma cells. The contribution of plasma cells to RFC is much greater in the high than in the low line. The cytodynamic and morphologic results presented in this article are compatible with the hypothesis that the group of genes segregated in each line during the selective breeding control and regulate the rate of multiplication and differentiation of the antibody-producing cells.

scholarly journals GENETIC CONTROL OF THE IMMUNE RESPONSE

1972 ◽  
Vol 135 (1) ◽  
pp. 126-135 ◽  
Author(s):  
Graham F. Mitchell ◽  
F. Carl Grumet ◽  
Hugh O. McDevitt
Keyword(s):  
Immune Response ◽  
Cell Interaction ◽  
Primary Response ◽  
High Response ◽  
High Responder ◽  
Igg Antibody ◽  
Low Responder ◽  
Freund’S Adjuvant ◽  
Freund's Adjuvant ◽  
Synthetic Polypeptide

The effect of thymectomy on the genetically controlled murine immune response-1 (Ir-1) to the synthetic polypeptide poly-L(Tyr, Glu)-poly-D, L-Ala--poly-L-Lys [(T, G)-A--L] was studied with both aqueous and adjuvant immunization regimens. Adult thymectomy (combined with irradiation and bone marrow transfusion) did not affect the aqueous antigen-induced (IgM) primary response of either high or low responder mice, but did ablate the (IgG) secondary or tertiary response, a response which is restricted to the high responder strains. Adult thymectomy also blocked the normal high response to (T,G)-A--L in Freund's adjuvant in high responder mice and the high response to methylated bovine serum albumin (MBSA)-(T,G)-A--L in low responder mice. Neonatal thymectomy was also effective in blocking the response to (T, G)-A--L in Freund's adjuvant in high responder mice. These data are consistent with the concept that the Ir-1 gene effect is mediated via thymus cell interaction with antigen and with "B"-cells during the time of induction of IgG antibody formation.

scholarly journals POS0461 RESPONSE TO BIOLOGIC THERAPY IN RHEUMATOID ARTHRITIS: RETHINKING OUR CLASSIFICATION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 462.1-462
Author(s):  
E. Vallejo-Yagüe ◽  
S. Kandhasamy ◽  
E. Keystone ◽  
A. Finckh ◽  
R. Micheroli ◽  
...  
Keyword(s):  
Treatment Response ◽  
Real World ◽  
Observational Studies ◽  
Initial Response ◽  
Primary Response ◽  
Sustained Response ◽  
Secondary Response ◽  
Real World Data ◽  
World Data ◽  
Secondary Failure

Background:In rheumatoid arthritis (RA), primary failure with biologic treatment may be understood as lack of initial clinical response, while secondary failure would be loss of effectiveness after an initial response. Despite these clinical concepts, there is no unifying operational definition of primary and secondary non-response to RA treatment in observational studies using real-world data. On top of data-driven challenges, when conceptualizing secondary non-responders, it is unclear if the mechanism behind loss of effectiveness after a brief initial response is similar to loss of effectiveness after previous benefit sustained over time.Objectives:This viewpoint aims to motivate discussion on how to define primary and secondary non-response in observational studies. Ultimately, we aim to trigger expert committees to develop standard terminology for these concepts.Methods:We discuss different methodologies for defining primary and secondary non-response in observational studies. To do so, we shortly overview challenges characteristic of performing observational studies in real-world data, and subsequently, we conceptualize whether treatment response should be a dichotomous classification (Primary response/non-response; Secondary response/non-response), or whether one should consider three response categories (Primary response/non-response; Primary sustained/non-sustained response; Secondary response/non-response).Results:RA or biologic registries are a common data source for studying treatment response in real-world data. While registries include disease-specific variables to assess disease progression, missing data, loss of follow-up, and visits restricted to the year or mid-year visit may present a challenge. We believe there is a general agreement to assess primary response within the first 6 month of treatment. However, conceptualizing secondary non-response, one could wonder if a patient with brief initial response and immediate loss of it should belong to the same response category as a patient who relapses after a period of prior benefit that was sustained over time. Until this concern is clarified, we recommend considering a period of sustained response as a pre-requisite for secondary failure. This would result in the following three categories: a) Primary non-response: Lack of response within the first 6 months of treatment; b) Primary sustained response: Maintenance of a positive effectiveness outcome for at least the first 12 months since treatment start; c) Secondary non-response: Loss of effectiveness after achieved primary sustained response. Figure 1 illustrates this classification through a decision tree. Since the underlying mechanisms for treatment failure may differ among the above-mentioned categories, we recommend to use the three-category classification. However, since this may pose additional methodological challenges in real-world data, optionally, a dichotomous 12-month time-point may be used to assess secondary non-response (unfavourable outcome after 12-months) in comparison to primary non-response or non-sustained response (unfavourable outcome within the first 12-months). Similarly, to study primary response, the solely 6-month timepoint may be used.Conclusion:A unified operational definition of treatment response will minimize heterogeneity among observational studies and help improve the ability to draw cross-study comparisons, which we believe would be of particular interest when identifying predictors of treatment failure. Thus, we hope to open the room for discussion and encourage expert committees to work towards a common approach to assess treatment primary and secondary non-response in RA in observational studies.Disclosure of Interests:Enriqueta Vallejo-Yagüe: None declared, Sreemanjari Kandhasamy: None declared, Edward Keystone Speakers bureau: Amgen, AbbVie, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Novartis, Pfizer Pharmaceuticals, Sanofi Genzyme, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb Company, Celltrion, Myriad Autoimmune, F. Hoffmann-La Roche Inc, Gilead, Janssen Inc, Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepsis, Grant/research support from: Amgen, Merck, Pfizer Pharmaceuticals, PuraPharm, Axel Finckh Speakers bureau: Pfizer, Eli-Lilly, Paid instructor for: Pfizer, Eli-Lilly, Consultant of: AbbVie, AB2Bio, BMS, Gilead, Pfizer, Viatris, Grant/research support from: Pfizer, BMS, Novartis, Raphael Micheroli Consultant of: Gilead, Eli-Lilly, Pfizer and Abbvie, Andrea Michelle Burden: None declared

T cell response to myoglobin: a comparison of T cell clones in high-responder and low-responder mice

1988 ◽  
Vol 18 (9) ◽  
pp. 1329-1335 ◽  
Author(s):  
Itsuo Gorai ◽  
Michiko Aihara ◽  
Garvin S. Bixler ◽  
M. Zouhair Atassi ◽  
Peter Walden ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
High Responder ◽  
T Cell Clones ◽  
Cell Clones ◽  
Low Responder

Cognate CD4 help is essential for the reactivation and expansion of CD8 memory T cells directed against the hematopoietic cell–specific dominant minor histocompatibility antigen, H60

Blood ◽  
2009 ◽  
Vol 113 (18) ◽  
pp. 4273-4280 ◽  
Author(s):  
Su Jeong Ryu ◽  
Kyung Min Jung ◽  
Hyun Seung Yoo ◽  
Tae Woo Kim ◽  
Sol Kim ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Primary Response ◽  
Hematopoietic Cell ◽  
Secondary Response ◽  
Memory Cd8 T Cells ◽  
Specific Memory ◽  
Cd4 Help ◽  
Different Response

AbstractIn contrast to previous notions of the help-independency of memory CD8 T cells during secondary expansion, here we show that CD4 help is indispensable for the re-expansion of once-helped memory CD8 T cells, using a hematopoietic cell–specific dominant minor histocompatibility (H) antigen, H60, as a model antigen. H60-specific memory CD8 T cells generated during a helped primary response vigorously expanded only when rechallenged under helped conditions. The help requirement for an optimal secondary response was confirmed by a reduction in peak size by CD4 depletion, and was reproduced after skin transplantation. Helpless conditions or noncognate separate help during the secondary response resulted in a significant reduction in the peak size and different response kinetics. Providing CD4 help again during a tertiary challenge restored robust memory expansion; however, the repeated deprivation of help further reduced clonal expansion. Adoptively transferred memory CD8 T cells did not proliferate in CD40L−/− hosts. In the CD40−/− hosts, marginal memory expansion was detected after priming with male H60 cells but was completely abolished by priming with peptide-loaded CD40−/− cells, suggesting the essential role of CD40 and CD40L in memory responses. These results provide insight into the control of minor H antigen-specific CD8 T-cell responses, to maximize the graft-versus-leukemia response.

scholarly journals Basal microRNA expression patterns in reward circuitry of selectively bred high-responder and low-responder rats vary by brain region and genotype

2014 ◽  
Vol 46 (8) ◽  
pp. 290-301 ◽  
Author(s):  
David E. Hamilton ◽  
Christopher L. Cooke ◽  
Bradley S. Carter ◽  
Huda Akil ◽  
Stanley J. Watson ◽  
...  
Keyword(s):  
Mental Health ◽  
Differential Expression ◽  
Mirna Expression ◽  
Brain Region ◽  
Expression Patterns ◽  
Mental Health Disorders ◽  
High Responder ◽  
Prelimbic Cortex ◽  
Low Responder ◽  
Health Disorders

Mental health disorders involving altered reward, emotionality, and anxiety are thought to result from the interaction of individual predisposition (genetic factors) and personal experience (environmental factors), although the mechanisms that contribute to an individual's vulnerability to these disorders remain poorly understood. We used an animal model of individual variation [inbred high-responder/low-responder (bHR-bLR) rodents] known to vary in reward, anxiety, and emotional processing to examine neuroanatomical expression patterns of microRNAs (miRNAs). Laser capture microdissection was used to dissect the prelimbic cortex and the nucleus accumbens core and shell prior to analysis of basal miRNA expression in bHR and bLR male rats. These studies identified 187 miRNAs differentially expressed by genotype in at least one brain region, 10 of which were validated by qPCR. Four of these 10 qPCR-validated miRNAs demonstrated differential expression across multiple brain regions, and all miRNAs with validated differential expression between genotypes had lower expression in bHR animals compared with bLR animals. microRNA (miR)-484 and miR-128a expression differences between the prelimbic cortex of bHR and bLR animals were validated by semiquantitative in situ hybridization. miRNA expression analysis independent of genotype identified 101 miRNAs differentially expressed by brain region, seven of which validated by qPCR. Dnmt3a mRNA, a validated target of miR-29b, varied in a direction opposite that of miR-29b's differential expression between bHR and bLR animals. These data provide evidence that basal central nervous system miRNA expression varies in the bHR-bLR model, implicating microRNAs as potential epigenetic regulators of key neural circuits and individual differences associated with mental health disorders.

Differential expression of Broad-Complex transcription factors may forecast tissue-specific developmental fates during Drosophila metamorphosis

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3275-3287 ◽  
Author(s):  
I.F. Emery ◽  
V. Bedian ◽  
G.M. Guild
Keyword(s):  
Western Blot ◽  
Expression Patterns ◽  
Primary Response ◽  
Protein Isoforms ◽  
Secondary Response ◽  
C Protein ◽  
Tissue Specific ◽  
Specific Outcome ◽  
C Proteins ◽  
Broad Complex

The steroid hormone ecdysone initiates metamorphosis in Drosophila melanogaster by activating a cascade of gene activity that includes primary response transcriptional regulators and secondary response structural genes. The Broad-Complex (BR-C) primary response gene is composed of several distinct genetic functions and encodes a family of related transcription factor isoforms. Our objective was to determine whether BR-C isoforms were components of the primary ecdysone response in all tissues and whether tissue-specific isoform expression is associated with tissue-specific metamorphic outcomes. We used specific antibody reagents that recognize and distinguish among the Z1, Z2 and Z3 BR-C protein isoforms to study protein expression patterns during the initial stages of metamorphosis. Western blot analyses demonstrated that BR-C isoforms are induced at the onset of metamorphosis, each with unique kinetics of induction and repression. Whole-mount immunostaining showed that the BR-C proteins accumulate in the nuclei of all larval and imaginal tissues indicating that the BR-C is induced as a primary response in many tissues. Several tissues express different levels and combinations of the BR-C isoforms suggesting that the BR-C is important in determining the tissue-specific outcome of many parallel ecdysone response cascades. For example, prepupal salivary glands (destined for histolysis during metamorphosis) express Z1 isoforms while imaginal discs (destined for cell differentiation and morphogenesis) shift from the synthesis of Z2 isoforms to the synthesis of Z1 isoforms. The prepupal central nervous system (destined for tissue remodeling) expresses all isoforms, with Z3 predominating. Salivary gland chromosome immunostaining indicated that BR-C proteins interact directly with numerous loci in the polytene genome. Finally, western blot analyses showed that distinct BR-C genetic functions can be correlated with single and specific BR-C protein isoforms.

scholarly journals Turbidity reduction in drinking water by coagulation-flocculation with chitosan polymers

2019 ◽  
Vol 17 (2) ◽  
pp. 204-218 ◽  
Author(s):  
Ampai Soros ◽  
James E. Amburgey ◽  
Christine E. Stauber ◽  
Mark D. Sobsey ◽  
Lisa M. Casanova
Keyword(s):  
Drinking Water ◽  
Functional Groups ◽  
Dose Range ◽  
Optimal Dose ◽  
Global Network ◽  
Point Of Zero Charge ◽  
Household Water ◽  
Generous Support ◽  
Higher Doses ◽  
Model Household

Abstract Turbidity reduction by coagulation-flocculation in drinking water reduces microbes and organic matter, increasing effectiveness of downstream treatment. Chitosan is a promising household water coagulant, but needs parameters for use. This study tested the effects of chitosan dose, molecular weight (MW), degree of deacetylation (DD), and functional groups on bentonite and kaolinite turbidity reduction in model household drinking water. Higher MW or DD produced greater reductions. Highest reductions were at doses 1 and 3 mg/L by MW >50,000 or >70% DD (residual turbidity <5 NTU). Higher doses did not necessarily continually increase reduction. For functional groups, 3 mg/L produced the highest reductions by lactate, acetate, and HCl, and lower reductions of kaolinite than bentonite. Doses where the point of zero charge was observed clustered around 3 mg/L. Chitosan reduced clay turbidity in water; effectiveness was influenced by dose, clay type, MW, DD, and functional groups. Reduction did not necessarily increase with MW. Bentonite had a broader effective dose range and higher reduction at the optimal dose than kaolinite. Chitosans with and without functional groups performed similarly. The best of the studied doses was 3 mg/L. Chitosans are promising for turbidity reduction in low-resource settings if combined with sedimentation and/or filtration. This article has been made Open Access thanks to the generous support of a global network of libraries as part of the Knowledge Unlatched Select initiative.

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