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JCI Insight Jan 2021Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune...
Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission, and we showed that the 127-hi cell population is a mix of Th1- and Th2-type cells, with a significant bias toward antiinflammatory Th2-type cells. In addition, we extended these findings to show that patients with the highest frequency of 127-hi cells at diagnosis were significantly more likely to maintain β cell function. Moreover, in patients treated with alefacept in the T1DAL clinical trial, the probability of responding favorably to the antiinflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an antiinflammatory environment that is permissive for partial remission, β cell survival, and response to antiinflammatory immunotherapy.
Topics: Adolescent; Adult; Alefacept; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Diabetes Mellitus, Type 1; Disease Progression; Female; Humans; Immunotherapy; Infant; Interleukin-2 Receptor alpha Subunit; Interleukin-7 Receptor alpha Subunit; Male; Multivariate Analysis; Proportional Hazards Models; T-Lymphocyte Subsets; Young Adult
PubMed: 33301420
DOI: 10.1172/jci.insight.136114 -
Medicine Mar 2022Given the high disability rate of multiple sclerosis (MS), there is a need for safer and more effective therapeutic agents. Existing literature highlights the prominent...
Given the high disability rate of multiple sclerosis (MS), there is a need for safer and more effective therapeutic agents. Existing literature highlights the prominent roles of miRNA in MS pathophysiology. Nevertheless, there are few studies that have explored the usefulness of existing drugs in treating MS through potential miRNA-modulating abilities.The current investigation identifies genes that may exacerbate the risk of MS due to their respective miRNA associations. These findings were then used to determine potential drug candidates through the construction of miRNA-regulated drug-pathway network through genes. We uncovered a total of 48 MS risk pathways, 133 MS risk miRNAs, and 186 drugs that can affect these pathways. Potential MS risk miRNAs that are also regulated by therapeutic candidates were hsa05215 and hsa05152. We analyzed the properties of the miRNA-regulated drug-pathway network through genes and uncovered a number of novel MS agents by assessing their respective Z-values.A total of 20 likely drug candidates were identified, including human immunoglobulin, aspirin, alemtuzumab, minocycline, abciximab, alefacept, palivizumab, bevacizumab, efalizumab, tositumomab, minocycline, etanercept, catumaxomab, and sarilumab. Each of these agents were then explored with regards to their likely mechanism of action in treating MS.The current investigation provides a fresh perspective on MS biological mechanisms as well as likely treatment strategies.
Topics: Alemtuzumab; Antineoplastic Agents; Drug Repositioning; Humans; MicroRNAs; Multiple Sclerosis
PubMed: 35356949
DOI: 10.1097/MD.0000000000029107 -
Frontiers in Immunology 2018Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be...
Elimination of the latent HIV reservoir remains the biggest hurdle to achieve HIV cure. In order to specifically eliminate HIV infected cells they must be distinguishable from uninfected cells. CD2 was recently identified as a potential marker enriched in the HIV-1 reservoir on CD4+ T cells, the largest, longest-lived and best-characterized constituent of the HIV reservoir. We previously proposed to repurpose FDA-approved alefacept, a humanized α-CD2 fusion protein, to reduce the HIV reservoir in CD2hi CD4+ memory T cells. Here, we show the first evidence that alefacept can specifically target and reduce CD2hi HIV infected cells . We explore a variety of natural killer (NK) cells as mediators of antibody-dependent cell-mediated cytotoxicity (ADCC) including primary NK cells, expanded NK cells as well as the CD16 transduced NK-92 cell line which is currently under study in clinical trials as a treatment for cancer. We demonstrate that CD16.NK-92 has a natural preference to kill CD2hi CD45RA- memory T cells, specifically CD45RA- CD27+ central memory/transitional memory (T) subset in both healthy and HIV patient samples as well as to reduce HIV DNA from HIV samples from donors well controlled on antiretroviral therapy. Lastly, alefacept can combine with CD16.NK-92 to decrease HIV DNA in some patient samples and thus may yield value as part of a strategy toward sustained HIV remission.
Topics: Adoptive Transfer; Alefacept; Anti-HIV Agents; Antibody-Dependent Cell Cytotoxicity; Biomarkers; CD2 Antigens; CD4-Positive T-Lymphocytes; Cell Line; DNA, Viral; Drug Therapy, Combination; GPI-Linked Proteins; HIV Infections; HIV-1; Humans; Immunologic Memory; Jurkat Cells; Killer Cells, Natural; Leukocyte Common Antigens; Receptors, IgG; Tumor Necrosis Factor Receptor Superfamily, Member 7; Virus Latency
PubMed: 30455699
DOI: 10.3389/fimmu.2018.02552 -
Frontiers in Medicine 2021Herpes zoster (HZ) has raised public concern. An increasing incidence of HZ can be seen in the immunocompromised population, such as the psoriasis patients taking...
Herpes zoster (HZ) has raised public concern. An increasing incidence of HZ can be seen in the immunocompromised population, such as the psoriasis patients taking biologics. Real-world evidences are still needed to investigate the risks of HZ among patients receiving different biologics treatments. This study aims to summarize the findings from cohort studies. Herein, we performed a meta-analysis of cohort studies. We included studies referred to seven biologics (adalimumab, alefacept, efalizumab, etanercept, infliximab, rituximab, and ustekinumab) as well as methotrexate for psoriasis. We estimated summary relative risks (RRs) for HZ using pairwise and network meta-analysis. Overall, five studies were included for analysis. A total of 32827.6 patient-years were observed. The result of the meta-analysis showed that the pooled HZ incidence rate of adalimumab, which accounts for the most patient-years in our analysis, is 2.6 per 1,000 patient-years. Our analysis based on several cohorts showed an insignificant difference among the patients receiving adalimumab, alefacept, efalizumab, etanercept, infliximab, rituximab, ustekinumab, and methotrexate. Based on this analysis, the type of mono-biologic treatment contributes little to the risk of HZ among psoriasis patients. Of note, the negative findings of our study do not mean the unnecessity of vaccination. More efforts must be taken to further determine HZ risk of different therapeutic strategies.
PubMed: 34150802
DOI: 10.3389/fmed.2021.665559 -
Transplantation Dec 2016Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a... (Review)
Review
BACKGROUND
Graft-versus-host-disease (GVHD) after liver transplantation (LT) is a deadly complication with very limited data on risk factors, diagnosis and management. We report a case series and a comprehensive review of the literature.
METHODS
Data were systematically extracted from reports of GVHD after LT, and from the United Network for Organ Sharing database. Group comparisons were performed.
RESULTS
One hundred fifty-six adult patients with GVHD after LT have been reported. Median time to GVHD onset was 28 days. Clinical features were skin rash (92%), pancytopenia (78%), and diarrhea (65%). Six-month mortality with GVHD after LT was 73%. Sepsis was the most common cause of death (60%). Enterobacter bacteremia, invasive aspergillosis, and disseminated Candida infections were frequently reported. Recipient age over 50 years is a risk factor for GVHD after LT. Hepatocellular carcinoma was overrepresented, whereas chronic hepatitis C was underrepresented, in reported United States GVHD cases relative to all United Network for Organ Sharing database LT cases. Mortality rate with treatment of GVHD after LT was 84% with high-dose steroids alone, 75% to 100% with regimens using dose increases of calcineurin inhibitors, and 55% with IL-2 antagonists. Mortality was 25% in small case series using the CD2-blocker alefacept or TNF-α antagonists.
CONCLUSIONS
Age older than 50 years and hepatocellular carcinoma appear to be risk factors for GVHD. Hepatitis C may be protective. High-dose steroids and calcineurin inhibitors are ineffective in the treatment of GVHD after LT. CD2-blockers and TNF-α antagonists appear promising. We propose a diagnostic algorithm to assist clinicians in managing adults with GVHD after LT.
Topics: Adolescent; Adult; Aged; Algorithms; Carcinoma, Hepatocellular; Databases, Factual; Diabetes Complications; Female; Graft vs Host Disease; Humans; Iowa; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Risk Factors; United States; Universities; Young Adult
PubMed: 27495762
DOI: 10.1097/TP.0000000000001406 -
The AAPS Journal Mar 2020Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly...
Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly abused drug. Our previously designed highly efficient cocaine hydrolases (CocHs) and the corresponding Fc-fusion proteins (e.g., CocH3-Fc) are recognized as potentially promising therapeutic enzyme candidates for cocaine abuse treatment, but all with limited biological half-lives. In order to prolong the biological half-life and, thus, decrease the required frequency of the enzyme administration for cocaine abuse treatment, we have modeled the Fc-fusion CocH binding with neonatal Fc receptor (FcRn) in the present study. This approach led to the design and testing of CocH3-Fc(M6), a CocH3-Fc mutant with nearly 100-fold increased binding affinity: from K = ~ 4 μM to K = 43 nM. As a result, CocH3-Fc(M6) indeed revealed a markedly prolonged biological half-life (t = 206 ± 7 h or ~ 9 days) in rats, longer than other known Fc-fusion protein drugs such as abatacept and alefacept (for other therapeutic purposes) in the same species (rats). It has been demonstrated that a single dose of 3 mg/kg CocH3-Fc(M6) effectively blocked 20 mg/kg cocaine-induced hyperactivity on day 18 after CocH3-Fc(M6) administration. This is the first attempt to rationally design long-acting Fc-fusion enzyme mutant based on combined computational modeling and experimental measurement of the Fc-fusion CocH binding with FcRn. The similar structure-based design strategy may be used to prolong the biological half-lives of other Fc-fusion protein drugs.
Topics: Animals; Carboxylic Ester Hydrolases; Cocaine-Related Disorders; Drug Design; Drug Evaluation, Preclinical; Half-Life; Histocompatibility Antigens Class I; Male; Models, Molecular; Rats; Rats, Sprague-Dawley; Receptors, Fc; Recombinant Fusion Proteins; Recombinant Proteins
PubMed: 32189158
DOI: 10.1208/s12248-020-00442-3 -
World Journal of Hepatology Apr 2015Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α...
Lymphomas may be induced by the systemic immunosuppressive therapies used to treat psoriasis, such as ciclosporin, methotrexate and tumour necrosis factor (TNF)-α blockers. The biologic agents currently used in psoriasis include alefacept, efalizumab, and the TNF-α antagonists etanercept, infliximab, and adalimumab. Infections and cancer are the main possible consequences of intended or unexpected immunosuppression. We report a 59-year-old man with a history of severe psoriasis vulgaris treated with traditional immunosuppressant drugs followed by anti-TNF-α therapy; the patient was firstly hospitalized for an acute cholestatic toxic hepatitis, which we supposed to be related to adalimumab. The first liver biopsy showed active disease with severe hepatocellular damage caused by heavy lymphocytes infiltrate in portal tracts at in the interface with a not conclusive diagnosis of lymphoproliferative disease. The correct diagnosis of T cell/histiocyte- rich large B cell lymphoma (T/HRBCL) was only reached through a gastric biopsy and a second liver biopsy. T/HRBCL is an uncommon morphologic variant of diffuse large B-cell lymphoma not described until now in psoriatic patients receiving immunosuppressive biologic agents. In psoriatic patients, treated with biologic immunosuppressive agents, the suspect of abdominal lymphoma should always be included as differential diagnosis. Abdominal ultrasound evaluation need therefore to be included in the pre-treatment screening as in the follow-up surveillance.
PubMed: 25914782
DOI: 10.4254/wjh.v7.i5.814 -
American Journal of Transplantation :... Mar 2015Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of...
Depletional strategies directed toward achieving tolerance induction in organ transplantation have been associated with an increased incidence and risk of antibody-mediated rejection (AMR) and graft injury. Our clinical data suggest correlation of increased serum B cell activating factor/survival factor (BAFF) with increased risk of antibody-mediated rejection in alemtuzumab treated patients. In the present study, we tested the ability of BAFF blockade (TACI-Ig) in a nonhuman primate AMR model to prevent alloantibody production and prolong allograft survival. Three animals received the AMR inducing regimen (CD3-IT/alefacept/tacrolimus) with TACI-Ig (atacicept), compared to five control animals treated with the AMR inducing regimen only. TACI-Ig treatment lead to decreased levels of DSA in treated animals at 2 and 4 weeks posttransplantation (p < 0.05). In addition, peripheral B cell numbers were significantly lower at 6 weeks posttransplantation. However, it provided only a marginal increase in graft survival (59 ± 22 vs. 102 ± 47 days; p = 0.11). Histological analysis revealed a substantial reduction in findings typically associated with humoral rejection with atacicept treatment. More T cell rejection findings were observed with increased graft T cell infiltration in atacicept treatment, likely secondary to the graft prolongation. We show that BAFF/APRIL blockade using concomitant TACI-Ig treatment reduced the humoral portion of rejection in our depletion-induced preclinical AMR model.
Topics: Animals; Antibodies, Neutralizing; Antibody Formation; B-Cell Activating Factor; Graft Survival; Humans; Kidney Transplantation; Lymphocyte Depletion; Macaca mulatta; Male; Models, Animal; Recombinant Fusion Proteins; T-Lymphocytes; Tumor Necrosis Factor Ligand Superfamily Member 13
PubMed: 25675879
DOI: 10.1111/ajt.13045 -
Journal of Diabetes Investigation Nov 2016
Topics: Alefacept; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Recombinant Fusion Proteins; Treatment Outcome
PubMed: 27181881
DOI: 10.1111/jdi.12501