Immunogenicity of bone morphogenetic proteins

Object The object of this paper is to review the immunogenicity of bone morphogenetic proteins (BMPs) and to compare the results of the immunogenicity characterization and clinical consequences between recombinant human (rh)BMP-2 and recombinant human osteogenic protein-1 (rhOP-1/BMP-7). Methods The immunogenicity of therapeutic proteins and its clinical effects were reviewed. The characteristics of BMPs were also described in terms of immunogenicity. The methods and results of antibody detection in various clinical trials of rhBMP-2 and rhOP-1 were compared, including the most recent studies using a systematic characterization strategy with both a binding assay and bioassay. Results Similar to all recombinant human proteins, rhBMPs induce immune responses in a select subgroup of patients. Adverse effects from this response in these patients, however, have not been reported with antibody formation to either rhBMP-2 or rhOP-1. Overall, the incidence of antibody formation was slightly higher in rhOP-1 trials than in rhBMP-2 trials. Conclusions Although they occur in a subgroup of patients, the immune responses against rhBMPs have no correlation with any clinical outcome or safety parameter. Clinicians, however, must be aware of the potential complications caused by the immunogenicity of BMPs until more studies clearly elucidate their safety.

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Major role of local immune responses in antibody formation to factor IX in AAV gene transfer

Gene Therapy ◽

10.1038/sj.gt.3302539 ◽

2005 ◽

Vol 12 (19) ◽

pp. 1453-1464 ◽

Cited By ~ 73

Author(s):

L Wang ◽

O Cao ◽

B Swalm ◽

E Dobrzynski ◽

F Mingozzi ◽

...

Keyword(s):

Gene Transfer ◽

Immune Responses ◽

Antibody Formation ◽

Factor Ix

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Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

International Journal of Molecular Sciences ◽

10.3390/ijms23020673 ◽

2022 ◽

Vol 23 (2) ◽

pp. 673

Author(s):

Vittoria Favero ◽

Arianna Cremaschi ◽

Chiara Parazzoli ◽

Alberto Falchetti ◽

Agostino Gaudio ◽

...

Keyword(s):

Subclinical Atherosclerosis ◽

Pituitary Tumors ◽

Bone Fragility ◽

Clinical Effects ◽

Cortisol Secretion ◽

Peripheral Tissues ◽

Dehydrogenase Enzyme ◽

Skin Fragility ◽

Clinical Consequences ◽

Peripheral Activation

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

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Visualizing antibody production in a human lymph node in a dish

Science Translational Medicine ◽

10.1126/scitranslmed.abg5638 ◽

2021 ◽

Vol 13 (578) ◽

pp. eabg5638

Author(s):

Gerald P. Morris

Keyword(s):

Lymph Node ◽

Immune Responses ◽

Antibody Production ◽

Antibody Formation ◽

In Vitro Modeling ◽

Human Lymph Node

Development of a human lymphoid organoid system enables in vitro modeling of immune responses and antibody formation.

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Clinical Consequences of Antibody Formation, Serum Concentrations, and HLA-Cw6 Status in Psoriasis Patients on Ustekinumab

Therapeutic Drug Monitoring ◽

10.1097/ftd.0000000000000646 ◽

2019 ◽

Vol 41 (5) ◽

pp. 634-639 ◽

Cited By ~ 2

Author(s):

Eline De Keyser ◽

Celine I. Busard ◽

Sven Lanssens ◽

Lieve Meuleman ◽

Barbara A. Hutten ◽

...

Keyword(s):

Antibody Formation ◽

Serum Concentrations ◽

Clinical Consequences

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Effect of probiotics supplementation on acute diarrhea in infants: a randomized double blind clinical trial

Paediatrica Indonesiana ◽

10.14238/pi47.4.2007.172-8 ◽

2007 ◽

Vol 47 (4) ◽

pp. 172

Author(s):

I Gusti Ngurah Sanjaya Putra ◽

Sudaryat Suraatmaja ◽

I Ketut Nomor Aryasa

Keyword(s):

Treatment Group ◽

Immune Responses ◽

Acute Diarrhea ◽

Relative Risk Reduction ◽

Cox Regression ◽

Clinical Effects ◽

Double Blind ◽

Standard Management ◽

Double Blind Clinical Trial ◽

The Mean

Background Probiotics has advantages as a supplement formanagement of infants with acute diarrhea. It influences theduration of diarrhea by enhancing immune responses, elaboratesantimicrobial substances and occupies intestinal mucosal sites,inhibits the attachment and the growth of pathogenic organismsby achieving competitive exclusion and microbial balance.Objective To assess the clinical effects of probiotics supplementationon acute diarrhea in infants.Methods This was a double blind, randomized clinical controlledtrial performed on infants aged 1-12 months old with acutediarrhea, hospitalized in Sanglah Hospital, Denpasar. Subjectswere divided into two groups; the treatment group had standardmanagement with adjuvant probiotics, while the control groupreceived standard management with placebo.Results From 70 infants enrolled in this study, the mean durationof diarrhea in treatment group was significantly shorter than thatin the placebo group, 49.03 hours (SE 3.09) (95%CI 42.98;55.08)vs 73.03 hours (SE 3.28) (95%CI 66.61;79.45); P=0.001.Regarding failure of the treatment, probiotics supplementationhad relative risk reduction (RRR) of 67% and absolute riskreduction (ARR) of 57%. In multivariate cox regression analysisit was found that only probiotics supplementation influenced theduration of acute diarrhea in infants.Conclusion Probiotics can shorten the duration of acute diarrhea,and is safe as an adjuvant to standard management for infantswith acute diarrhea.

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Immune Responses of Iranian Patients with Visceral Leishmaniasis and Recovered Individuals to LCR1 of Leishmania infantum

Clinical and Vaccine Immunology ◽

10.1128/cvi.00711-13 ◽

2014 ◽

Vol 21 (4) ◽

pp. 518-525 ◽

Cited By ~ 1

Author(s):

Hamid M. Niknam ◽

Firoozeh Abrishami ◽

Mohammad Doroudian ◽

Mosayeb Rostamian ◽

Maryam Moradi ◽

...

Keyword(s):

Visceral Leishmaniasis ◽

Immune Responses ◽

Leishmania Infantum ◽

Mononuclear Cells ◽

Antibody Responses ◽

Antibody Detection ◽

Recent History ◽

Content Type ◽

History Of ◽

Ifn Γ

ABSTRACTVisceral leishmaniasis is a serious public health problem.Leishmania infantumis one of its causative agents. LCR1 is an immunogen fromL. infantum. Antibodies against this protein have been detected in visceral leishmaniasis patients. The aim of this study was to define the antibody and cellular immune responses against LCR1 in Iranian visceral leishmaniasis patients and recovered individuals. The LCR1 protein was produced in recombinant form. Antibody responses against this protein were studied in Iranian individuals with a recent history of visceral leishmaniasis. Responses of peripheral blood mononuclear cells to this protein were studied in Iranian individuals who had recovered from visceral leishmaniasis. Our data show that (i) there was an antibody response to LCR1 in each individual with a recent history of visceral leishmaniasis studied, (ii) there was neither a proliferative response nor production of gamma interferon (IFN-γ) or interleukin 10 in response to LCR1 by mononuclear cells from individuals who had recovered from visceral leishmaniasis, and (iii) individuals who have recovered from visceral leishmaniasis show ongoing immune responses long after recovery from the disease. These data show that there are no detectable cellular memory responses to LCR1 in Iranian individuals who have recovered from visceral leishmaniasis, while there are detectable antibody responses in patients with this disease. Our data suggest that LCR1 has potential applications for the diagnosis of leishmaniasis through antibody detection, while the application of LCR1 alone for induction of IFN-γ in individuals who recovered from this disease is not supported. The presence of long-lasting immune reactivities in individuals who recovered from the disease may show the necessity of extended medical surveillance for these individuals.

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High-Dose RHAMM-R3 Peptide Peptide Vaccination for Patients with Vaccination for Patients with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM) and Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v112.11.2911.2911 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2911-2911 ◽

Cited By ~ 1

Author(s):

Jochen Greiner ◽

Anita Schmitt ◽

Krzysztof Giannopoulos ◽

Isabel Funk ◽

Marta Heyduk ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

T Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Residual Disease ◽

Lymphocytic Leukemia ◽

High Dose ◽

Clinical Effects ◽

Peptide Vaccination

Abstract We have demonstrated immunological responses and positive clinical effects of a peptide vaccination for patients with AML, MDS, MM and CLL with a limited tumor load or a minimal residual disease over-expressing RHAMM using 300 μg RHAMM-R3 peptide (Schmitt et al., Blood 2008; Giannopoulos et al., abstract submitted). To date, 26 patients were enrolled in this clinical peptide vaccination trial. Here, we report on the second cohort of nine patients with AML, MDS and MM vaccinated with a higher peptide dose (1000 μg RHAMM-R3 peptide). The vaccine was given four times at a biweekly interval and GM-CSF was added for five days each vaccination. Similar to the patients vaccinated with 300 μg peptide only mild drug-related adverse events were observed such as erythema and induration of the skin. Immunomonitoring was performed using ELISpot assays for Interferon gamma and Granzyme B, tetramer-based flow cytometry and chromium release assays. Moreover, the frequency of regulatory T cells was quantified at different time points of vaccination. In this second cohort of patients treated with 1,000 μg peptide we detected specific immune responses in a lower frequency (4/9 patients) in contrast to patients in the 300 μg cohort (7/10 patients). In these patients with immune responses we found an increase of CD8+/HLA-A2/RHAMM-R3 tetramer+/CD45RA+/CCR7−/CD27−/CD28− effector T cells in flow cytometry in accordance with an increase of R3-specific CD8+ T cells in ELISpot assays. Two patients with positive immune responses showed a significant decrease of regulatory T cells. One patient without positive immune and clinical effects showed an increase of the frequency of regulatory T cells (5.03% to 15.9%). Three out of nine patients treated with 1,000 μg showed positive clinical effects: One patient with MDS RAEB-2 showed a reduction of leukemic blasts in the bone morrow to lower than 5%, one MDS patient achieved a normalization of the peripheral blood counts and one patient with multiple myeloma experienced a reduction of light chain in serum. The patients in the 300 μg cohort showed also a higher frequency of positive clinical effects (5 out of 10 patients). Taken together, RHAMM-R3 peptide vaccination induced both immunological and clinical responses. Therefore, RHAMM constitutes a promising structure for further targeted immunotherapies in patients with different hematological malignancies. However, higher doses of peptide do not improve the frequency and intensity of immune responses in this clinical trial.

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Co-Existing Serological Immune Responses against RHAMM Might Be a Prerequisite for Strong Cellular Immune Responses of CD8-Positive T Cells in RHAMM-R3 Peptide Vaccination for Patients with Different Hematological Malignancies.

Blood ◽

10.1182/blood.v114.22.3671.3671 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3671-3671

Author(s):

Jochen Greiner ◽

Susanne Hofmann ◽

Krzysztof Giannopoulos ◽

Markus Rojewski ◽

Anna Babiak ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Responses ◽

High Dose ◽

Clinical Effects ◽

Peptide Vaccination ◽

Cell Responses ◽

Tetramer Staining

Abstract Abstract 3671 Poster Board III-607 For effective elimination of malignant cells by specific T cells a co-activation of CD4- and CD8-positive T cells might be important. We performed two RHAMM-R3 peptide vaccination trials using 300μg and 1000μg for patients with AML, MDS and multiple myeloma overexpressing RHAMM. Similar mild toxicity of both cohorts was found, only mild drug-related adverse events were observed such as erythema and induration of the skin. In the 300μg cohort we detected in 7/10 (70 %) patients specific immune responses and also positive clinical effects in 5/10 (50 %) patients. In the high dose peptide vaccination trial (1000μg peptide) 4/9 (44 %) patients showed positive immune responses. These patients showed an increase of CD8+RHAMM-R3 tetramer+/CD45RA+/CCR7-/CD27-/CD28- effector T cells and an increase of R3-specific CD8+ T cells. In the higher peptide dose cohort three patients showed positive clinical effects. However, higher doses of peptide do not improve the frequency and intensity of immune responses in this clinical trial and might induce immune tolerance. In this work, we investigated the co-existence of serological immune responses against RHAMM detected by a RHAMM-specific ELISA of patients with AML, MDS and multiple myeloma treated in these two peptide vaccination trials. We correlated these results to specific T cell responses of CD8-positive T cells measured by ELISpot assays for interferon gamma and Granzyme B, tetramer staining and chromium release assays. Moreover, these results were compared to the frequency of regulatory T cells. 4/19 patients have a positive serological immune response in ELISA assay, all of these patients developed also strong specific CD8-positive T cell responses during peptide vaccination detected by ELISpot assays and tetramer staining. As expected, peptide vaccination did not result in the induction of humoral immune responses. In further ELISA assays we measured IL-2 and IL-10 levels in the sera of the patients before and three weeks after four vaccinations. While IL-10 levels remained at a rather low level over the time of vaccination, we detected an increase of IL-2 up to the five-fold of the initial levels in four of ten patients. Moreover, we performed a proteome array to detect cytokine and chemokine regulation in sera of patients vaccinated in these two trials during and after RHAMM-R3 peptide vaccination. 36 cytokines, chemokines and acute phase proteins were measured and both cohorts vaccinated with different peptide doses were compared. Taken together, RHAMM-R3 peptide vaccination induced both immunological and clinical responses. Co-existence of immune responses of CD4-positive T cells against the target RHAMM seems to be important for an induction of strong immune responses of CD8-positive T cells. Disclosures: No relevant conflicts of interest to declare.

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A novel recombinant tandem repeat DNA vaccine targeting at MUC1

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.3066 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 3066-3066

Author(s):

W. Wu ◽

D. Jin ◽

W. Lou ◽

J. Fan ◽

D. Wang ◽

...

Keyword(s):

Immune Responses ◽

Western Blot ◽

Dna Vaccine ◽

Tandem Repeat ◽

Blot Analysis ◽

Western Blot Analysis ◽

Antibody Detection ◽

Mucin 1 ◽

Cytotoxic Assay ◽

Transfection Assay

3066 Background: Tandem repeat (TR) is the key epitope of mucin 1 (MUC1) for inducing cytotoxic T lymphocytes (CTL) to kill the tumor cells specifically. A novel recombinant TR DNA vaccine was constructed to study its induced immune responses. Methods: A recombinant human TR (rhTR) gene encoding a single TR polypeptide of MUC1 was synthesized and cloned into the multiple cloning sites of plasmid pcDNA3.1/Myc-his (+) A to construct the recombinant plasmid pcDNA3.1-TR/Myc-his (+) A (pTR plasmid). Expression of pTR plasmid was confirmed by transfection assay and Western blot analysis. C57BL/6 (H-2b) mice were immunized with pTR plasmid (n=15) by tibial muscle injection. Mice inoculated with the empty vector (EV group, n=15) and 0.9% NaCl solution (NS group, n=15) were used as vector and blank control respectively. Four weeks later, all mice were immunized again. Specific antibody detection and cytotoxic assay were used to evaluate the vaccine-induced TR specific immune responses. Results: DNA sequencing confirmed that the pTR plasmid was exactly constructed. Transfection assay and Western blot analysis found that the transfected COS7 cells expressed TR polypeptide of MUC1 48 hours after transfection. Cytotoxic assay showed that immunization with pTR plasmid into C57BL/6 mice resulted in more efficient induction of CTL specific cytolysis against TR polypeptide than that of EV group and NS group (p<0.01). Vaccine immunized mice had a higher equivalent concentration of anti-TR specific antibodies (2324μg/ml±238μg/ml) than that of EV group (1896μg/ml±533μg/ml, p<0.01) and NS group (1736μg/ml±142μg/ml, p<0.01). Conclusions: The novel recombinant TR DNA vaccine targeting at MUC1 was exactly constructed, immunization with which could induce TR specific CTL response and antibodies response in mice. No significant financial relationships to disclose.

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