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Agnieszka Czechowicz, MD, PhD

Work and Education

Professional Education

Stanford University School of Medicine Registrar, Palo Alto, CA, 01/12/2012

Residency

Boston Children's Hospital Training Verifications, Boston, MA, 1/11/2015

Fellowship

Boston Children's Hospital Training Verifications, Boston, MA, 02/01/2017

Stanford University Pediatric Hematology Oncology Fellowship, Palo Alto, CA, 12/31/2017

Conditions Treated

Bone Marrow Failure Disorders

Fanconi Anemia

Stem Cell Transplant

All Publications

Anti-CD117 antibody depletes normal and myelodysplastic syndrome human hematopoietic stem cells in xenografted mice. Blood Pang, W. W., Czechowicz, A., Logan, A. C., Bhardwaj, R., Poyser, J., Park, C. Y., Weissman, I. L., Shizuru, J. A. 2019

Abstract

The myelodysplastic syndromes (MDS) represent a group of clonal disorders that result in ineffective hematopoiesis and are associated with an increased risk of transformation into acute leukemia. MDS arises from hematopoietic stem cells (HSCs); therefore, successful elimination of MDS HSCs is an important part of any curative therapy. However, current treatment options, including allogeneic hematopoietic cell transplantation (HCT), often fail to ablate disease-initiating MDS HSCs, and thus have low curative potential and high relapse rates. Here, we demonstrate that human HSCs can be targeted and eliminated by monoclonal antibodies (mAbs) that bind cell surface CD117 (c-Kit). We show that an anti-human CD117 mAb, SR-1, inhibits normal cord blood and bone marrow HSCs in vitro. Further, SR-1 and clinical-grade humanized anti-human CD117 mAb, AMG 191, deplete normal and MDS HSCs in vivo in xenograft mouse models. Anti-CD117 mAbs also facilitate the engraftment of normal donor human HSCs in MDS xenograft mouse models, restoring normal human hematopoiesis and eradicating aggressive pathologic MDS cells. This study is the first to demonstrate that anti-human CD117 mAbs have potential as novel therapeutics to eradicate MDS HSCs and augment the curative effect of allogeneic HCT for this disease. Moreover, we establish the foundation for use of these antibody agents not only in the treatment of MDS but for the multitude of other HSC-driven blood and immune disorders for which transplant can be disease-altering.

View details for PubMedID 30745302

Hematopoietic chimerism and donor-specific skin allograft tolerance after non-genotoxic CD117 antibody-drug-conjugate conditioning in MHC-mismatched allotransplantation. Nature communications Li, Z., Czechowicz, A., Scheck, A., Rossi, D. J., Murphy, P. M. 2019; 10 (1): 616

Abstract

Hematopoietic chimerism after allogeneic bone marrow transplantation may establish a state of donorantigen-specific tolerance. However, current allotransplantation protocols involve genotoxic conditioning which has harmful side-effects and predisposes to infection and cancer. Here we describe a non-genotoxic conditioning protocol for fully MHC-mismatched bone marrow allotransplantation in mice involving transient immunosuppression and selective depletion of recipient hematopoietic stem cells with a CD117-antibody-drug-conjugate (ADC). This protocol resulted in multilineage, high level (up to 50%), durable, donor-derived hematopoietic chimerism after transplantation of 20 million total bone marrow cells, compared with 2.1% hematopoietic chimerism from 50 million total bone marrow cells without conditioning. Moreover, long-term survival of bone marrow donor-type but not third partyskin allografts is achieved in CD117-ADC-conditioned chimeric mice without chronic immunosuppression. The only observed adverse event is transient elevation of liver enzymes in the first week after conditioning. These results provide proof-of-principle for CD117-ADC as a non-genotoxic, highly-targeted conditioning agent in allotransplantation and tolerance protocols.

View details for PubMedID 30728353

Selective hematopoietic stem cell ablation using CD117-antibody-drug-conjugates enables safe and effective transplantation with immunity preservation. Nature communications Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Hoggatt, J., Saez, B., Pang, W. W., Mansour, M. K., Tate, T. A., Chan, Y. Y., Walck, E., Wernig, G., Shizuru, J. A., Winau, F., Scadden, D. T., Rossi, D. J. 2019; 10 (1): 617

Abstract

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for blood and immune diseases with potential for many settings beyond current standard-of-care. Broad HSCT application is currently precluded largely due to morbidity and mortality associated with genotoxic irradiation or chemotherapy conditioning. Here we show that a single dose of a CD117-antibody-drug-conjugate (CD117-ADC) to saporin leads to>99% depletion of host HSCs, enabling rapid and efficient donor hematopoietic cell engraftment. Importantly, CD117-ADC selectively targets hematopoietic stem cells yet does not cause clinically significant side-effects. Blood counts and immune cell function are preserved following CD117-ADC treatment, with effective responses by recipients to both viral and fungal challenges. These results suggest that CD117-ADC-mediated HSCT pre-treatment could serve as a non-myeloablative conditioning strategy for the treatment of a wide range of non-malignant and malignant diseases, and might be especially suited to gene therapy and gene editing settings in which preservation of immunity is desired.

View details for PubMedID 30728354

Clonal-level lineage commitment pathways of hematopoietic stem cells in vivo. Proceedings of the National Academy of Sciences of the United States of America Lu, R., Czechowicz, A., Seita, J., Jiang, D., Weissman, I. L. 2019

Abstract

While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been perturbed by irradiation or by an antagonistic anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiate. Some of these clones dominantly expand and exhibit lineage bias. We identified the cellular origins of clonal dominance and lineage bias and uncovered the lineage commitment pathways that lead HSC clones to different levels of self-renewal and blood production under various transplantation conditions. This study reveals surprising alterations in HSC fate decisions directed by conditioning and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.

View details for PubMedID 30622181

Anti-human CD117 antibody-mediated bone marrow niche clearance in non-human primates and humanized NSG mice. Blood Kwon, H., Logan, A. C., Chhabra, A., Pang, W. W., Czechowicz, A., Tate, K., Le, A., Poyser, J., Hollis, R., Kelly, B. V., Kohn, D. B., Weissman, I. L., Prohaska, S. S., Shizuru, J. A. 2019

View details for PubMedID 30617195

Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches SCIENCE Czechowicz, A., Kraft, D., Weissman, I. L., Bhattacharya, D. 2007; 318 (5854): 1296-1299

Abstract

Upon intravenous transplantation, hematopoietic stem cells (HSCs) can home to specialized niches, yet most HSCs fail to engraft unless recipients are subjected to toxic preconditioning. We provide evidence that, aside from immune barriers, donor HSC engraftment is restricted by occupancy of appropriate niches by host HSCs. Administration of ACK2, an antibody that blocks c-kit function, led to the transient removal of >98% of endogenous HSCs in immunodeficient mice. Subsequent transplantation of these mice with donor HSCs led to chimerism levels of up to 90%. Extrapolation of these methods to humans may enable mild but effective conditioning regimens for transplantation.

View details for DOI 10.1126/science.1149726

View details for Web of Science ID 000251086600042

View details for PubMedID 18033883

View details for PubMedCentralID PMC2527021

Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice. Blood advances Gao, C., Schroeder, J. A., Xue, F., Jing, W., Cai, Y., Scheck, A., Subramaniam, S., Rao, S., Weiler, H., Czechowicz, A., Shi, Q. 2019; 3 (18): 27002711

Abstract

Gene therapy offers the potential to cure hemophilia A (HA). We have shown that hematopoietic stem cell (HSC)-based platelet-specific factor VIII (FVIII) (2bF8) gene therapy can produce therapeutic protein and induce antigen-specific immune tolerance in HA mice, even in the presence of inhibitory antibodies. For HSC-based gene therapy, traditional preconditioning using cytotoxic chemotherapy or total body irradiation (TBI) has been required. The potential toxicity associated with TBI or chemotherapy is a deterrent that may prevent patients with HA, a nonmalignant disease, from agreeing to such a protocol. Here, we describe targeted nongenotoxic preconditioning for 2bF8 gene therapy utilizing a hematopoietic cell-specific antibody-drug conjugate (ADC), which consists of saporin conjugated to CD45.2- and CD117-targeting antibodies. We found that a combination of CD45.2- and CD117-targeting ADC preconditioning was effective for engrafting 2bF8-transduced HSCs and was favorable for platelet lineage reconstitution. Two thirds of HA mice that received 2bF8 lentivirus-transduced HSCs under (CD45.2+CD117)-targeting ADC conditioning maintained sustained therapeutic levels of platelet FVIII expression. When CD8-targeting ADC was supplemented, chimerism and platelet FVIII expression were significantly increased, with long-term sustained platelet FVIII expression in all primary and secondary recipients. Importantly, immune tolerance was induced and hemostasis was restored in a tail-bleeding test, and joint bleeding also was effectively prevented in a needle-induced knee joint injury model in HA mice after 2bF8 gene therapy. In summary, we show for the first time efficient engraftment of gene-modified HSCs without genotoxic conditioning. The combined cocktail ADC-mediated hematopoietic cell-targeted nongenotoxic preconditioning that we developed is highly effective and favorable for platelet-specific gene therapy in HA mice.

View details for DOI 10.1182/bloodadvances.2019000516

View details for PubMedID 31515232

Anti-CD117 antibody depletes normal and myelodysplastic syndrome human hematopoietic stem cells in xenografted mice BLOOD Pang, W. W., Czechowicz, A., Logan, A. C., Bhardwaj, R., Poyser, J., Park, C. Y., Weissman, I. L., Shizuru, J. A. 2019; 133 (19): 206978
Anti-human CD117 antibody-mediated bone marrow niche clearance in nonhuman primates and humanized NSG mice BLOOD Kwon, H., Logan, A. C., Chhabra, A., Pang, W. W., Czechowicz, A., Tate, K., Le, A., Poyser, J., Hollis, R., Kelly, B. V., Kohn, D. B., Weissman, I. L., Prohaska, S. S., Shizuru, J. A. 2019; 133 (19): 21048
The MarrowMiner: A Novel Minimally Invasive and Effective Device for the Harvest of Bone Marrow. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Kraft, D., Walck, E., Carrasco, A., Crocker, M., Song, L., Long, M., Mosse, M., Nadeem, B., Imanbyev, G., Czechowicz, A., McCullough, M. 2019

Abstract

Bone marrow (BM) is a rich source of hematopoietic stem cells (HSC), mesenchymal stem cells (MSC) and other important stem/progenitor cells. It is the traditional source of cells utilized in hematopoietic cell transplantation (HCT), which is a proven curative treatment for many blood and immune diseases. BM-derived cells have also been shown to have other diverse clinical uses and are increasingly being utilized in orthopedic, regenerative medicine, and gene therapy applications. Traditional methods for harvesting BM are crude, tedious, time-consuming and expensive; requiring multiple bone punctures under general anesthesia with serial small volume aspirates often diluted with peripheral blood. The MarrowMiner (MM) is a novel device designed for rapid and minimally invasive BM harvest. Here we show the safety and efficacy of the MM in both preclinical and clinical settings. In a large-animal porcine model, the MM enabled effective BM collection with similar total nucleated cell collection and increased colony formation (CFU-F) compared to standard methods. The MM was subsequently evaluated in a clinical study showing effective and complication-free anterior and posterior BM collection of 20 subjects under only local anesthesia or light sedation. Increased total nucleated and mononucleated cell collection was achieved with the MM compared to standard methods in the same subjects. Importantly, stem cell content was high with trends towards increased HSC, MSC and endothelial progenitor cells with similar T-cell content. Given the MarrowMiner is a novel, FDA-approved device, enabling safe, effective and minimally invasive harvest of BM we anticipate rapid adoption for various applications.

View details for DOI 10.1016/j.bbmt.2019.08.027

View details for PubMedID 31491487

Selective HSC-Ablation Using CD117 Antibody-Drug-Conjugates Enables Safe and Effective Murine and Human Hematopoietic Stem Cell Transplantation Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Hoggatt, J., Saez, B., Pang, W. W., Mansour, M. K., Shizuru, J. A., Winau, F., Scadden, D. T., Rossi, D. J. CELL PRESS. 2018: 2324
Safe and Effective Platelet-Targeted Gene Therapy of Hemophilia A Enabled Using Non-Genotoxic, Antibody-Drug-Conjugate Conditioning Gao, C., Schroeder, J., Czechowicz, A., Shi, Q. CELL PRESS. 2018: 25
Immune Sparing Conditioning for BMT/HSCT Using Anti-Ckit Immunotoxins Czechowicz, A., Palchaudhuri, R., Scheck, A., Hu, Y., Winau, F., Hoggatt, J., Saez, B., Mansour, M. K., Sykes, D., Scadden, D., Rossi, D. ELSEVIER SCIENCE INC. 2018: S60S61
Anti-Human CD117 Antibodies Mediate Clearance of Myelodysplastic Syndrome Hematopoietic Stem Cells and Facilitate Establishment of Normal Hematopoiesis in Transplantation Pang, W. W., Czechowicz, A., Poyser, J., Park, C. Y., Weissman, I. L., Shizuru, J. A. ELSEVIER SCIENCE INC. 2018: S230S231
Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin NATURE BIOTECHNOLOGY Palchaudhuri, R., Saez, B., Hoggatt, J., Schajnovitz, A., Sykes, D. B., Tate, T. A., Czechowicz, A., Kfoury, Y., Ruchika, F. N., Rossi, D. J., Verdine, G. L., Mansour, M. K., Scadden, D. T. 2016; 34 (7): 738-?

Abstract

Hematopoietic stem cell transplantation (HSCT) offers curative therapy for patients with hemoglobinopathies, congenital immunodeficiencies, and other conditions, possibly including AIDS. Autologous HSCT using genetically corrected cells would avoid the risk of graft-versus-host disease (GVHD), but the genotoxicity of conditioning remains a substantial barrier to the development of this approach. Here we report an internalizing immunotoxin targeting the hematopoietic-cell-restricted CD45 receptor that effectively conditions immunocompetent mice. A single dose of the immunotoxin, CD45-saporin (SAP), enabled efficient (>90%) engraftment of donor cells and full correction of a sickle-cell anemia model. In contrast to irradiation, CD45-SAP completely avoided neutropenia and anemia, spared bone marrow and thymic niches, enabling rapid recovery of T and B cells, preserved anti-fungal immunity, and had minimal overall toxicity. This non-genotoxic conditioning method may provide an attractive alternative to current conditioning regimens for HSCT in the treatment of non-malignant blood diseases.

View details for DOI 10.1038/nbt.3584

View details for Web of Science ID 000381335400028

View details for PubMedID 27272386

View details for PubMedCentralID PMC5179034

A trial of plerixafor adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency PEDIATRIC TRANSPLANTATION Dvorak, C. C., Horn, B. N., Puck, J. M., Czechowicz, A., Shizuru, J. A., Ko, R. M., Cowan, M. J. 2014; 18 (6): 602-608

Abstract

For infants with SCID, the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with G-CSF plus plerixafor given to the host to mobilize HSC from their niches. We enrolled six patients who received CD34-selected haploidentical cells and one who received T-replete matched unrelated BM. All patients receiving G-CSF and plerixafor had generally poor CD34(+) cell and Lin(-) CD34(+) CD38(-) CD90(+) CD45RA(-) HSC mobilization, and developed donor T cells, but no donor myeloid or B-cell engraftment. Although well tolerated, G-CSF plus plerixafor alone failed to overcome physical barriers to donor engraftment.

View details for DOI 10.1111/petr.12309

View details for Web of Science ID 000340530800017

View details for PubMedCentralID PMC5413354

A trial of alemtuzumab adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency PEDIATRIC TRANSPLANTATION Dvorak, C. C., Horn, B. N., Puck, J. M., Adams, S., Veys, P., Czechowicz, A., Cowan, M. J. 2014; 18 (6): 609-616

Abstract

For infants with SCID the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled four patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The two patients who engrafted had delayed T-cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T-cell development in patients with SCID in the setting of a T-cell depleted graft.

View details for DOI 10.1111/petr.12310

View details for Web of Science ID 000340530800018

View details for PubMedID 24977928

View details for PubMedCentralID PMC4134761

In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice. Blood Derderian, S. C., Togarrati, P. P., King, C., Moradi, P. W., Reynaud, D., Czechowicz, A., Weissman, I. L., MacKenzie, T. C. 2014; 124 (6): 973-980

Abstract

Although in utero hematopoietic cell transplantation is a promising strategy to treat congenital hematopoietic disorders, levels of engraftment have not been therapeutic for diseases in which donor cells have no survival advantage. We used an antibody against the murine c-Kit receptor (ACK2) to deplete fetal host hematopoietic stem cells (HSCs) and increase space within the hematopoietic niche for donor cell engraftment. Fetal mice were injected with ACK2 on embryonic days 13.5 to 14.5 and surviving pups were transplanted with congenic hematopoietic cells on day of life 1. Low-dose ACK2 treatment effectively depleted HSCs within the bone marrow with minimal toxicity and the antibody was cleared from the serum before the neonatal transplantation. Chimerism levels were significantly higher in treated pups than in controls; both myeloid and lymphoid cell chimerism increased because of higher engraftment of HSCs in the bone marrow. To test the strategy of repeated HSC depletion and transplantation, some mice were treated with ACK2 postnatally, but the increase in engraftment was lower than that seen with prenatal treatment. We demonstrate a successful fetal conditioning strategy associated with minimal toxicity. Such strategies could be used to achieve clinically relevant levels of engraftment to treat congenital stem cell disorders.

View details for DOI 10.1182/blood-2014-02-550327

View details for PubMedID 24879814

Anti-KIT monoclonal antibody inhibits imatinib-resistant gastrointestinal stromal tumor growth PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Edris, B., Willingham, S. B., Weiskopf, K., Volkmer, A. K., Volkmer, J., Muehlenberg, T., Montgomery, K. D., Contreras-Trujillo, H., Czechowicz, A., Fletcher, J. A., West, R. B., Weissman, I. L., van de Rijn, M. 2013; 110 (9): 3501-3506

Abstract

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract and arises from the interstitial cells of Cajal. It is characterized by expression of the receptor tyrosine kinase CD117 (KIT). In 70-80% of GIST cases, oncogenic mutations in KIT are present, leading to constitutive activation of the receptor, which drives the proliferation of these tumors. Treatment of GIST with imatinib, a small-molecule tyrosine kinase inhibitor, inhibits KIT-mediated signaling and initially results in disease control in 70-85% of patients with KIT-positive GIST. However, the vast majority of patients eventually develop resistance to imatinib treatment, leading to disease progression and posing a significant challenge in the clinical management of these tumors. Here, we show that an anti-KIT monoclonal antibody (mAb), SR1, is able to slow the growth of three human GIST cell lines in vitro. Importantly, these reductions in cell growth were equivalent between imatinib-resistant and imatinib-sensitive GIST cell lines. Treatment of GIST cell lines with SR1 reduces cell-surface KIT expression, suggesting that mAb-induced KIT down-regulation may be a mechanism by which SR1 inhibits GIST growth. Furthermore, we also show that SR1 treatment enhances phagocytosis of GIST cells by macrophages, indicating that treatment with SR1 may enhance immune cell-mediated tumor clearance. Finally, using two xenotransplantation models of imatinib-sensitive and imatinib-resistant GIST, we demonstrate that SR1 is able to strongly inhibit tumor growth in vivo. These results suggest that treatment with mAbs targeting KIT may represent an alternative, or complementary, approach for treating GIST.

View details for DOI 10.1073/pnas.1222893110

View details for PubMedID 23382202

Anti-CD117 (c-Kit) Monoclonal Antibodies Deplete Human Hematopoietic Stem Cells and Facilitate Their Replacement in Humanized NOD/SCID/IL2R gamma(-/-) Mice: A Non-Toxic Conditioning Regimen for Allotransplantation Logan, A. C., Czechowicz, A., Kelley, B. V., Thway, T. M., Magana, I., Krampf, M. R., Poyser, J., Hollis, R. P., Kohn, D. B., Weissman, I. L., Shizuru, J. A. AMER SOC HEMATOLOGY. 2012
Clonal Level Lineage Commitment of Mouse Hematopoietic Stem Cells in Vivo 54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Lu, R., Czechowicz, A., Seita, J., Weissman, I. L. AMER SOC HEMATOLOGY. 2012
Transplantation Conditioning Regimens Induce Different Hematopoietic Stem Cell Differentiation in Mice At the Clonal Level 53rd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Lu, R., Czechowicz, A., Weissman, I. L. AMER SOC HEMATOLOGY. 2011: 6767
Purified Hematopoietic Stem Cell Transplantation: The Next Generation of Blood and Immune Replacement HEMATOLOGY-ONCOLOGY CLINICS OF NORTH AMERICA Czechowicz, A., Weissman, I. L. 2011; 25 (1): 75-?

Abstract

Replacement of disease-causing stem cells with healthy ones has been achieved clinically via hematopoietic cell transplantation (HCT) for the last 40 years, as a treatment modality for a variety of cancers and immunodeficiencies with moderate, but increasing, success. This procedure has traditionally included transplantation of mixed hematopoietic populations that include hematopoietic stem cells (HSC) and other cells, such as T cells. This article explores and delineates the potential expansion of this technique to treat a variety of inherited diseases of immune function, the current barriers in HCT and pure HSC transplantation, and the up-and-coming strategies to combat these obstacles.

View details for DOI 10.1016/j.hoc.2010.11.006

View details for Web of Science ID 000287333600007

View details for PubMedID 21236391

Targeted Clearance of Human Hematopoietic Stem Cell Niches Via Inhibition of SCF Signaling Using Monoclonal Antibody SR-1 52nd Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) Czechowicz, A., Bhardwaj, R., Park, C. Y., Weissman, I. L. AMER SOC HEMATOLOGY. 2010: 3940
Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ahn, G., Tseng, D., Liao, C., Dorie, M. J., Czechowicz, A., Brown, J. M. 2010; 107 (18): 8363-8368

Abstract

Despite recent advances in radiotherapy, loco-regional failures are still the leading cause of death in many cancer patients. We have previously reported that bone marrow-derived CD11b(+) myeloid cells are recruited to tumors grown in irradiated tissues, thereby restoring the vasculature and tumor growth. In this study, we examined whether neutralizing CD11b monoclonal antibodies could inhibit the recruitment of myeloid cells into irradiated tumors and inhibit their regrowth. We observed a significant enhancement of antitumor response to radiation in squamous cell carcinoma xenografts in mice when CD11b antibodies are administered systemically. Histological examination of tumors revealed that CD11b antibodies reduced infiltration of myeloid cells expressing S100A8 and matrix metalloproteinase-9. CD11b antibodies further inhibited bone marrow-derived cell adhesion and transmigration to C166 endothelial cell monolayers and chemotactic stimuli, respectively, to levels comparable to those from CD11b knockout or CD18 hypomorphic mice. Given the clinical availability of humanized CD18 antibodies, we tested two murine tumor models in CD18 hypomorphic or CD11b knockout mice and found that tumors were more sensitive to irradiation when grown in CD18 hypomorphic mice but not in CD11b knockout mice. When CD18 hypomorphism was partially rescued by reconstitution with the wild-type bone marrow, the resistance of the tumors to irradiation was restored. Our study thus supports the rationale of using clinically available Mac-1 (CD11b/CD18) antibodies as an adjuvant therapy to radiotherapy.

View details for DOI 10.1073/pnas.0911378107

View details for Web of Science ID 000277310400058

View details for PubMedID 20404138

View details for PubMedCentralID PMC2889597

Purified Hematopoietic Stem Cell Transplantation: The Next Generation of Blood and Immune Replacement IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA Czechowicz, A., Weissman, I. L. 2010; 30 (2): 159-?

Abstract

Replacement of disease-causing stem cells with healthy ones has been achieved clinically via hematopoietic cell transplantation (HCT) for the last 40 years, as a treatment modality for a variety of cancers and immunodeficiencies with moderate, but increasing, success. This procedure has traditionally included transplantation of mixed hematopoietic populations that include hematopoietic stem cells (HSC) and other cells, such as T cells. This article explores and delineates the potential expansion of this technique to treat a variety of inherited diseases of immune function, the current barriers in HCT and pure HSC transplantation, and the up-and-coming strategies to combat these obstacles.

View details for DOI 10.1016/j.iac.2010.03.003

View details for Web of Science ID 000279115200003

View details for PubMedID 20493393

View details for PubMedCentralID PMC3071240

Niche recycling through division-independent egress of hematopoietic stem cells JOURNAL OF EXPERIMENTAL MEDICINE Bhattacharya, D., Czechowicz, A., Ooi, A. G., Rossi, D. J., Bryder, D., Weissman, I. L. 2009; 206 (12): 2837-2850

Abstract

Hematopoietic stem cells (HSCs) are thought to reside in discrete niches through stable adhesion, yet previous studies have suggested that host HSCs can be replaced by transplanted donor HSCs, even in the absence of cytoreductive conditioning. To explain this apparent paradox, we calculated, through cell surface phenotyping and transplantation of unfractionated blood, that approximately 1-5% of the total pool of HSCs enters into the circulation each day. Bromodeoxyuridine (BrdU) feeding experiments demonstrated that HSCs in the peripheral blood incorporate BrdU at the same rate as do HSCs in the bone marrow, suggesting that egress from the bone marrow to the blood can occur without cell division and can leave behind vacant HSC niches. Consistent with this, repetitive daily transplantations of small numbers of HSCs administered as new niches became available over the course of 7 d led to significantly higher levels of engraftment than did large, single-bolus transplantations of the same total number of HSCs. These data provide insight as to how HSC replacement can occur despite the residence of endogenous HSCs in niches, and suggest therapeutic interventions that capitalize upon physiological HSC egress.

View details for DOI 10.1084/jem.20090778

View details for Web of Science ID 000272079300020

View details for PubMedID 19887396

View details for PubMedCentralID PMC2806613

Niche Recycling through Division-Independent Egress of Hematopoietic Stem Cells. 51st Annual Meeting and Exposition of the American-Society-of-Hematology Czechowicz, A., Bhattacharya, D., Ooi, L., Rossi, D. J., Bryder, D., Weissman, I. L. AMER SOC HEMATOLOGY. 2009: 3737
Hematopoietic stem cell quiescence attenuates DNA damage response and permits DNA damage accumulation during aging CELL CYCLE Rossi, D. J., Seita, J., Czechowicz, A., Bhattacharya, D., Bryder, D., Weissman, I. L. 2007; 6 (19): 2371-2376

Abstract

The aging of tissue-specific stem and progenitor cells is believed to be central to the pathophysiological conditions arising in aged individuals. While the mechanisms driving stem cell aging are poorly understood, mounting evidence points to age-dependent DNA damage accrual as an important contributing factor. While it has been postulated that DNA damage may deplete stem cell numbers with age, recent studies indicate that murine hematopoietic stem cell (HSC) reserves are in fact maintained despite the accrual of genomic damage with age. Evidence suggests this to be a result of the quiescent (G0) cell cycle status of HSC, which results in an attenuation of checkpoint control and DNA damage responses for repair or apoptosis. When aged stem cells that have acquired damage are called into cycle under conditions of stress or tissue regeneration however, their functional capacity was shown to be severely impaired. These data suggest that age-dependent DNA damage accumulation may underlie the diminished capacity of aged stem cells to mediate a return to homeostasis after acute stress or injury. Moreover, the cytoprotection afforded by stem cell quiescence in stress-free, steady-state conditions suggests a mechanism through which potentially dangerous lesions can accumulate in the stem cell pool with age.

View details for Web of Science ID 000251085700012

View details for PubMedID 17700071

Adult human hematopoietic cells differentiate into mature T cells via a CD3-4+8-intermediate within the mouse thymic microenvironment; A new model system for the study of human thymocyte development. 47th Annual Meeting of the American-Society-of-Hematology Kraft, D. L., Czechowicz, A., Weissman, I. L. AMER SOC HEMATOLOGY. 2005: 155A156A