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Article ; Online: Transplantation after CD45-ADC corrects Rag1 immunodeficiency in congenic and haploidentical settings.

Pala, Francesca / Corsino, Cristina / Calzoni, Enrica / Villa, Anna / Pittaluga, Stefania / Palchaudhuri, Rahul / Bosticardo, Marita / Notarangelo, Luigi D

The Journal of allergy and clinical immunology

2023 Volume 153, Issue 1, Page(s) 341–348.e3

Abstract: Background: Mutations in the recombinase-activating genes 1 and 2 (RAG1, RAG2) cause a spectrum of phenotypes, ranging from severe combined immune deficiency to combined immune deficiency with immune dysregulation (CID-ID). Hematopoietic cell ... ...

Abstract	Background: Mutations in the recombinase-activating genes 1 and 2 (RAG1, RAG2) cause a spectrum of phenotypes, ranging from severe combined immune deficiency to combined immune deficiency with immune dysregulation (CID-ID). Hematopoietic cell transplantation is a curative option. Use of conditioning facilitates robust and durable stem cell engraftment and immune reconstitution but may cause toxicity. Transplantation from haploidentical donors is associated with poor outcome in patients with CID-ID. Objectives: We sought to evaluate multilineage engraftment and immune reconstitution after conditioning with CD45-antibody drug conjugate (CD45-ADC) as a single agent in hypomorphic mice with Rag1 mutation treated with congenic and haploidentical hematopoietic cell transplantation. Methods: Rag1-F971L mice, a model of CID-ID, were conditioned with various doses of CD45-ADC, total body irradiation, or isotype-ADC, and then given transplants of total bone marrow cells from congenic or haploidentical donors. Flow cytometry was used to assess chimerism and immune reconstitution. Histology was used to document reconstitution of thymic architecture. Results: Conditioning with CD45-ADC as a single agent allowed robust engraftment and immune reconstitution, with restoration of thymus, bone marrow, and peripheral compartments. The optimal doses of CD45-ADC were 1.5 mg/kg and 5 mg/kg for congenic and haploidentical transplantation, respectively. No graft-versus-host disease was observed. Conclusions: Conditioning with CD45-ADC alone allows full donor chimerism and immune reconstitution in Rag1 hypomorphic mice even following haploidentical transplantation, opening the way for the implementation of similar approaches in humans.
MeSH term(s)	Humans ; Mice ; Animals ; Transplantation Conditioning ; Hematopoietic Stem Cell Transplantation ; Bone Marrow Transplantation ; Immunologic Deficiency Syndromes/therapy ; Graft vs Host Disease ; Homeodomain Proteins/genetics
Chemical Substances	Homeodomain Proteins
Language	English
Publishing date	2023-08-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2023.07.017
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Article ; Online: Clearing and replacing tissue-resident myeloid cells with an anti-CD45 antibody-drug conjugate.

Gustafsson, Karin / Rhee, Catherine / Frodermann, Vanessa / Scadden, Elizabeth W / Li, Dan / Iwamoto, Yoshiko / Palchaudhuri, Rahul / Hyzy, Sharon L / Boitano, Anthony E / Nahrendorf, Matthias / Scadden, David T

Blood advances

2023 Volume 7, Issue 22, Page(s) 6964–6973

Abstract: Tissue-resident myeloid (TRM) cells in adults have highly variable lifespans, and may be derived from early embryonic yolk sac, fetal liver, or bone marrow. Some of these TRM cells are known pathogenic participants in congenital and acquired diseases. ... ...

Abstract	Tissue-resident myeloid (TRM) cells in adults have highly variable lifespans, and may be derived from early embryonic yolk sac, fetal liver, or bone marrow. Some of these TRM cells are known pathogenic participants in congenital and acquired diseases. Myeloablative conditioning and hematopoietic stem cell transplantation can replace long-lived brain TRM cells, resulting in clinical improvements in metabolic storage diseases. With the advent of antibody-drug conjugate (ADC)-targeted cell killing as a cell-selective means of transplant conditioning, we assessed the impact of anti-CD45-ADC on TRM cells in multiple tissues. Replacement of TRM cells ranged from 40% to 95% efficiencies in liver, lung, and skin tissues, after a single anti-CD45-ADC dose and bone marrow hematopoietic cell transfer. Of note, the population size of TRM cells in tissues returned to pretreatment levels, suggesting a regulated control of TRM cell abundance. As expected, brain microglia were not affected, but brain monocytes and macrophages were 50% replaced. Anti-CD45-ADC and adoptive cell transfer were then tested in the chronic acquired condition, atherosclerosis exacerbated by Tet2 mutant clonal hematopoiesis. Plaque-resident myeloid cells were efficiently replaced with anti-CD45-ADC and wild-type bone marrow cells. Notably, this reduced existent atherosclerotic plaque burden. Overall, these results indicate that the anti-CD45-ADC clears both hematopoietic stem and TRM cells from their niches, enabling cell replacement to achieve disease modification in a resident myeloid cell-driven disease.
MeSH term(s)	Adult ; Humans ; Immunoconjugates/pharmacology ; Macrophages ; Monocytes ; Bone Marrow ; Microglia
Chemical Substances	Immunoconjugates
Language	English
Publishing date	2023-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2023010561
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Article: CD45-antibody-drug conjugate clears tissue resident myeloid cells from their niches enabling therapeutic adoptive cell transfer.

bioRxiv : the preprint server for biology

2023

Abstract: Tissue resident myeloid cells (TRM) in adults have highly variable lifespans and may be derived from early embryonic yolk sac, fetal liver or bone marrow. Some of these TRM are known pathogenic participants in congenital and acquired diseases. ... ...

Abstract	Tissue resident myeloid cells (TRM) in adults have highly variable lifespans and may be derived from early embryonic yolk sac, fetal liver or bone marrow. Some of these TRM are known pathogenic participants in congenital and acquired diseases. Myeloablative conditioning and hematopoietic stem cell transplant can replace long-lived brain TRM resulting in clinical improvements in metabolic storage diseases. With the advent of antibody-drug-conjugate (ADC) targeted cell killing as a cell selective means of transplant conditioning, we assessed the impact of anti-CD45-ADC on TRM in multiple tissues. Replacement of TRM ranged from 40 to 95 percent efficiencies in liver, lung, and skin tissues, after a single anti-CD45-ADC dose and bone marrow hematopoietic cell transfer. Of note, the population size of TRM in tissues returned to pre-treatment levels suggesting a regulated control of TRM abundance. As expected, brain, microglia were not affected, but brain monocytes and macrophages were 50% replaced. Anti-CD45-ADC and adoptive cell transfer were then tested in the chronic acquired condition, atherosclerosis exacerbated by
Language	English
Publishing date	2023-09-07
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.09.05.556397
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Article ; Online: Alloengraftment without significant toxicity or GVHD in CD45 antibody-drug conjugate conditioned Fanconi anemia mice.

Blood

2024

Abstract: Fanconi anemia (FA) is an inherited DNA repair disorder characterized by bone marrow (BM) failure, developmental abnormalities, myelodysplasia, and leukemia and solid tumor predisposition. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a ...

Abstract	Fanconi anemia (FA) is an inherited DNA repair disorder characterized by bone marrow (BM) failure, developmental abnormalities, myelodysplasia, and leukemia and solid tumor predisposition. Allogeneic hematopoietic stem cell transplantation (allo-HSCT), a mainstay treatment, is limited by conditioning regimen-related toxicity and graft-versus-host disease (GVHD). Antibody-drug-conjugates (ADCs) targeting hematopoietic stem cells (HSCs) can open marrow niches permitting donor stem cell alloengraftment. Here, we report that single dose anti-mouse CD45-targeted-ADC (CD45-ADC) facilitated stable, multilineage chimerism in 3 distinct FA mouse models representing 90% of FA complementation groups. CD45-ADC profoundly depleted host stem cell enriched LineageSca1+cKit+ cells within 48 hours. Fanca-/- recipients of minor-mismatched BM and single dose CD45-ADC had peripheral blood (PB) mean donor chimerism >90%; donor HSCs alloengraftment was verified in secondary recipients. In Fancc-/- and Fancg-/- recipients of fully allogeneic grafts, PB mean donor chimerism was 60-80% and 70-80%, respectively. The mean percent donor chimerism in BM and spleen mirrored PB results. CD45-ADC conditioned mice did not have clinical toxicity. A transient <2.5-fold increase in hepatocellular enzymes and mild-to-moderate histopathological changes were seen. Under GVHD allo-HSCT conditions, wildtype and Fanca-/- recipients of CD45-ADC had markedly reduced GVHD lethality compared to lethal irradiation. Moreover, single dose anti-human CD45-ADC given to rhesus macaque nonhuman primates on days -6 or -10 was at least as myeloablative as lethal irradiation. These data suggest that CD45-ADC can potently promote donor alloengraftment and hematopoiesis without significant toxicity or severe GVHD, as seen with lethal irradiation, providing strong support for clinical trial considerations in highly vulnerable FA patients.
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023023549
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Article ; Online: Preadmission Cannabis Use Is Positively Correlated With Inpatient Opioid Dose Exposure in Hospitalized Patients With Inflammatory Bowel Diseases.

Dalal, Rahul S / Palchaudhuri, Sonali / Snider, Christopher K / Lewis, James D / Mehta, Shivan J / Lichtenstein, Gary R

Inflammatory bowel diseases

2020 Volume 27, Issue 4, Page(s) 500–506

Abstract: Background: Opioid use is associated with excess mortality in patients with inflammatory bowel disease (IBD). Recent data have highlighted that inpatient opioid exposure is associated with postdischarge opioid use in this population. It is unknown if ... ...

Abstract	Background: Opioid use is associated with excess mortality in patients with inflammatory bowel disease (IBD). Recent data have highlighted that inpatient opioid exposure is associated with postdischarge opioid use in this population. It is unknown if preadmission use of cannabis, which is commonly used for symptom relief among patients with IBD, increases the risk for inpatient opioid exposure when patients lack access to cannabis for symptom management. We sought to determine the association between preadmission cannabis use and inpatient opioid exposure while adjusting for relevant confounders. Methods: We performed a retrospective cohort study of adult patients hospitalized for IBD within a large academic health system from March 1, 2017, to April 10, 2018. Opioid exposure was calculated by converting the sum of administered opioid doses to intravenous morphine milligram equivalents and dividing by length of stay. We used multivariable linear regression to assess the association between cannabis use and inpatient opioid exposure while adjusting for confounders including IBD severity and preadmission opioid use. Results: Our study included 423 IBD patients. Linear regression analysis showed a significant positive correlation between inpatient opioid exposure (intravenous morphine milligram equivalents divided by length of stay) and preadmission cannabis use (coefficient = 12.1; 95% confidence interval [CI], 2.6-21.5). Other significantly associated variables were first patient-reported pain score (coefficient = 1.3; 95% CI, 0.6-2.0) and preadmission opioid use (coefficient = 22.3; 95% CI, 17.0-27.6). Conclusions: Cannabis use is positively correlated with inpatient opioid exposure after controlling for confounders. A personalized pain management approach should be considered to limit inpatient and possibly future opioid exposure among hospitalized patients with IBD who use cannabis.
MeSH term(s)	Adult ; Analgesics, Opioid/administration & dosage ; Cannabis/adverse effects ; Humans ; Inflammatory Bowel Diseases/drug therapy ; Inpatients ; Morphine Derivatives ; Pain Management ; Patient Discharge ; Retrospective Studies
Chemical Substances	Analgesics, Opioid ; Morphine Derivatives
Language	English
Publishing date	2020-05-14
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1340971-2
ISSN	1536-4844 ; 1078-0998
ISSN (online)	1536-4844
ISSN	1078-0998
DOI	10.1093/ibd/izaa104
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Article ; Online: Fertility-preserving myeloablative conditioning using single-dose CD117 antibody-drug conjugate in a rhesus gene therapy model.

Uchida, Naoya / Stasula, Ulana / Demirci, Selami / Germino-Watnick, Paula / Hinds, Malikiya / Le, Anh / Chu, Rebecca / Berg, Alexander / Liu, Xiong / Su, Ling / Wu, Xiaolin / Krouse, Allen E / Linde, N Seth / Bonifacino, Aylin / Hong, So Gun / Dunbar, Cynthia E / Lanieri, Leanne / Bhat, Anjali / Palchaudhuri, Rahul /

Bennet, Bindu / Hoban, Megan / Bertelsen, Kirk / Olson, Lisa M / Donahue, Robert E / Tisdale, John F

Nature communications

2023 Volume 14, Issue 1, Page(s) 6291

Abstract: Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds ... ...

Abstract	Hematopoietic stem cell (HSC) gene therapy has curative potential; however, its use is limited by the morbidity and mortality associated with current chemotherapy-based conditioning. Targeted conditioning using antibody-drug conjugates (ADC) holds promise for reduced toxicity in HSC gene therapy. Here we test the ability of an antibody-drug conjugate targeting CD117 (CD117-ADC) to enable engraftment in a non-human primate lentiviral gene therapy model of hemoglobinopathies. Following single-dose CD117-ADC, a >99% depletion of bone marrow CD34 + CD90 + CD45RA- cells without lymphocyte reduction is observed, which results are not inferior to multi-day myeloablative busulfan conditioning. CD117-ADC, similarly to busulfan, allows efficient engraftment, gene marking, and vector-derived fetal hemoglobin induction. Importantly, ADC treatment is associated with minimal toxicity, and CD117-ADC-conditioned animals maintain fertility. In contrast, busulfan treatment commonly causes severe toxicities and infertility in humans. Thus, the myeloablative capacity of single-dose CD117-ADC is sufficient for efficient engraftment of gene-modified HSCs while preserving fertility and reducing adverse effects related to toxicity in non-human primates. This targeted conditioning approach thus provides the proof-of-principle to improve risk-benefit ratio in a variety of HSC-based gene therapy products in humans.
MeSH term(s)	Animals ; Busulfan/pharmacology ; Genetic Therapy/methods ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells ; Immunoconjugates/pharmacology ; Proto-Oncogene Proteins c-kit/immunology ; Proto-Oncogene Proteins c-kit/therapeutic use ; Macaca mulatta/immunology
Chemical Substances	Busulfan (G1LN9045DK) ; Immunoconjugates ; Proto-Oncogene Proteins c-kit (EC 2.7.10.1)
Language	English
Publishing date	2023-10-12
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-41153-5
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Article ; Online: A CD45-targeted antibody-drug conjugate successfully conditions for allogeneic hematopoietic stem cell transplantation in mice.

Saha, Asim / Hyzy, Sharon / Lamothe, Tahirih / Hammond, Katelyn / Clark, Nicholas / Lanieri, Leanne / Bhattarai, Prashant / Palchaudhuri, Rahul / Gillard, Geoffrey O / Proctor, Jennifer / Riddle, Megan J / Panoskaltsis-Mortari, Angela / MacMillan, Margaret L / Wagner, John E / Kiem, Hans-Peter / Olson, Lisa M / Blazar, Bruce R

Blood

2022 Volume 139, Issue 11, Page(s) 1743–1759

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment of patients with nonmalignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current systemic nontargeted ... ...

Abstract	Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment of patients with nonmalignant or malignant blood disorders. Its success has been limited by graft-versus-host disease (GVHD). Current systemic nontargeted conditioning regimens mediate tissue injury and potentially incite and amplify GVHD, limiting the use of this potentially curative treatment beyond malignant disorders. Minimizing systemic nontargeted conditioning while achieving alloengraftment without global immune suppression is highly desirable. Antibody-drug-conjugates (ADCs) targeting hematopoietic cells can specifically deplete host stem and immune cells and enable alloengraftment. We report an anti-mouse CD45-targeted-ADC (CD45-ADC) that facilitates stable murine multilineage donor cell engraftment. Conditioning with CD45-ADC (3 mg/kg) was effective as a single agent in both congenic and minor-mismatch transplant models resulting in full donor chimerism comparable to lethal total body irradiation (TBI). In an MHC-disparate allo-HSCT model, pretransplant CD45-ADC (3 mg/kg) combined with low-dose TBI (150 cGy) and a short course of costimulatory blockade with anti-CD40 ligand antibody enabled 89% of recipients to achieve stable alloengraftment (mean value: 72%). When CD45-ADC was combined with pretransplant TBI (50 cGy) and posttransplant rapamycin, cyclophosphamide (Cytoxan), or a JAK inhibitor, 90% to 100% of recipients achieved stable chimerism (mean: 77%, 59%, 78%, respectively). At a higher dose (5 mg/kg), CD45-ADC as a single agent was sufficient for rapid, high-level multilineage chimerism sustained through the 22 weeks observation period. Therefore, CD45-ADC has the potential utility to confer the benefit of fully myeloablative conditioning but with substantially reduced toxicity when given as a single agent or at lower doses in conjunction with reduced-intensity conditioning.
MeSH term(s)	Animals ; Chimerism ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation/adverse effects ; Immunoconjugates/pharmacology ; Immunoconjugates/therapeutic use ; Immunoconjugates/toxicity ; Mice ; Transplantation Conditioning/methods
Chemical Substances	Immunoconjugates
Language	English
Publishing date	2022-01-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021012366
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Article ; Online: Transcript profiling and RNA interference as tools to identify small molecule mechanisms and therapeutic potential.

Palchaudhuri, Rahul / Hergenrother, Paul J

ACS chemical biology

2010 Volume 6, Issue 1, Page(s) 21–33

Abstract: The identification of the mechanism of action and therapeutic potential of bioactive small molecules remains a considerable challenge in the field of drug discovery and chemical biology. Apart from traditional target identification techniques, new tools ... ...

Abstract	The identification of the mechanism of action and therapeutic potential of bioactive small molecules remains a considerable challenge in the field of drug discovery and chemical biology. Apart from traditional target identification techniques, new tools have emerged that can significantly aid mechanism elucidation efforts. The development of pattern matching algorithms that compare transcription profile data to analogous data on compounds with known cellular targets allows for mechanistic insights without the need to synthesize chemically modified probes. In addition, such methods can be used to connect small molecules to particular disease states, thus aiding the rational identification of candidate therapeutics. Another method with considerable potential is whole-genome RNAi screening, a technique that can identify critical upstream proteins involved in a small molecule's mechanism of action. Several proof-of-concept studies using compounds with known cellular targets suggest this tool will enable mechanistic characterization of bioactive small molecules with unknown mechanisms. This Review highlights recent successes in using these pattern matching and chemical genetic tools, with the goal of uncovering small molecule mechanisms and identifying therapeutic candidates for disease treatment.
MeSH term(s)	Drug Design ; Pharmaceutical Preparations ; Protein Array Analysis/methods ; RNA Interference/drug effects ; RNA Precursors/drug effects ; RNA Precursors/genetics ; RNA, Small Interfering/drug effects ; RNA, Small Interfering/genetics
Chemical Substances	Pharmaceutical Preparations ; RNA Precursors ; RNA, Small Interfering
Language	English
Publishing date	2010-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/cb100310h
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Article ; Online: Exposure to Intravenous Opioids Is Associated With Future Exposure to Opioids in Hospitalized Patients With Inflammatory Bowel Diseases.

Dalal, Rahul S / Palchaudhuri, Sonali / Snider, Christopher K / Lewis, James D / Mehta, Shivan J / Lichtenstein, Gary R

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association

2019 Volume 18, Issue 10, Page(s) 2269–2278.e3

Abstract: Background & aims: Opioid use is associated with increased mortality in patients with inflammatory bowel diseases (IBD). Hospitalized patients with IBD often receive high-potency intravenous opioids (IVOPIs). It is not known whether exposure to IVOPIs ... ...

Abstract	Background & aims: Opioid use is associated with increased mortality in patients with inflammatory bowel diseases (IBD). Hospitalized patients with IBD often receive high-potency intravenous opioids (IVOPIs). It is not known whether exposure to IVOPIs affects post-discharge opioid use or complications. We investigated the association between inpatient administration of IVOPIs and a post-discharge opioid prescription (OPIRx) in patients with IBD. Methods: We performed a retrospective cohort study of 862 adults with IBD hospitalized at a large urban academic health system from March 1, 2017 through April 10, 2018. We collected clinical data from the electronic health records and used multivariable mixed-effect logistic regression to assess the association between inpatient opioid exposure and OPIRx-within 12 months while adjusting for confounders. IV and non-IVOPI exposures were evaluated as binary variables. IVOPI exposure was also evaluated as a continuous variable in IV morphine mg equivalents/length of stay (IVMMEs/day). Results: Multivariable mixed-effect logistic regression demonstrated a significant association between IVOPIs and OPIRx (IV vs no IVOPIs odds ratio [OR], 3.3; 95% CI, 1.7-6.4 and IVMMEs/day OR, 1.1; 95% CI, 1.0-1.1). Subgroup analysis of patients with IBD flares (n = 621) identified a significant association between IVOPIs and OPIRx (IV vs no IVOPIs OR, 5.4; 95% CI, 2.6-11.0). Among patients who did not receive IVOPIs, there was a significant association between oral/transdermal opioids and OPIRx (non-IVOPIs vs no opioids OR, 4.2; 95% CI, 1.0-16.8). Conclusions: Inpatient IV and non-IV opioid use are associated with post-discharge opioid exposure in patients with IBD, with a dose-dependent effect. Alternative analgesics should be considered for hospitalized patients with IBD, to minimize risk of future opioid use.
MeSH term(s)	Adult ; Aftercare ; Analgesics, Opioid/adverse effects ; Humans ; Inflammatory Bowel Diseases/complications ; Inflammatory Bowel Diseases/drug therapy ; Patient Discharge ; Retrospective Studies
Chemical Substances	Analgesics, Opioid
Language	English
Publishing date	2019-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2119789-1
ISSN	1542-7714 ; 1542-3565
ISSN (online)	1542-7714
ISSN	1542-3565
DOI	10.1016/j.cgh.2019.12.024
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Zs.A 5836: Show issues

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Article ; Online: Glutamate induces neutrophil cell migration by activating class I metabotropic glutamate receptors.

Gupta, Rahul / Palchaudhuri, Santanu / Chattopadhyay, Dhrubajyoti

Amino acids

2013 Volume 44, Issue 2, Page(s) 757–767

Abstract: Leukocytes are recruited at the site of infection or injury as a part of the innate immune system, and play a very critical role in fighting the invading microorganisms and/or healing wounds. Neutrophils are the most abundant leukocytes in healthy humans ...

Abstract	Leukocytes are recruited at the site of infection or injury as a part of the innate immune system, and play a very critical role in fighting the invading microorganisms and/or healing wounds. Neutrophils are the most abundant leukocytes in healthy humans and are the principal cell types that arrive at the target site in the initial phase of this process. Previous studies from our laboratory have shown that the amino acid glutamate is a novel chemotaxis-inducing factor for human neutrophils. In this report, we provide evidences that clearly demonstrate that the glutamate-induced neutrophil cell migration activity is mediated by the class I metabotropic glutamate receptors. Our results further show that a specific integrin β2 (ITG β2) receptor, namely LFA1 (α(L)β(2)) is activated upon glutamate treatment and is required for further downstream signaling events leading to increased migration of human neutrophil cells. Following glutamate stimulation, LFA1 is phosphorylated by the Src Kinase Lck at the Y735 residue, which triggers a downstream signaling cascade leading to activation of PI3K, Syk, Vav and finally the Rho family GTPase, Rac2. Interestingly, glutamate was previously found to be present in elevated levels in wound fluid. Furthermore, glutamate level was also found to go up following inflammation. Taken together, our study suggests a novel mode of neutrophil recruitment to the target site following an infection or injury.
MeSH term(s)	Cell Movement ; Cells, Cultured ; Glutamic Acid/immunology ; Humans ; Inflammation/immunology ; Neutrophil Infiltration ; Neutrophils/cytology ; Neutrophils/immunology ; Receptors, Metabotropic Glutamate/genetics ; Receptors, Metabotropic Glutamate/immunology ; Signal Transduction
Chemical Substances	Receptors, Metabotropic Glutamate ; Glutamic Acid (3KX376GY7L)
Language	English
Publishing date	2013-02
Publishing country	Austria
Document type	Journal Article
ZDB-ID	1121341-3
ISSN	1438-2199 ; 0939-4451
ISSN (online)	1438-2199
ISSN	0939-4451
DOI	10.1007/s00726-012-1400-1
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