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1.
Bone Marrow Transplant ; 52(4): 570-573, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28067886

ABSTRACT

We developed a haploidentical transplantation protocol with post-transplant cyclophosphamide (CY) for in vivo T-cell depletion (TCD) using a novel adapted-dosing schedule (25 mg/kg on days +3 and +4) for Fanconi anemia (FA). With median follow-up of 3 years (range, 37 days to 6.2 years), all six patients engrafted. Two patients with multiple pre-transplant comorbidities died, one from sepsis and one from sepsis with associated chronic GVHD. Four patients without preexisting comorbidities and early transplant referrals are alive with 100% donor chimerism and excellent performance status. We conclude that adjusted-dosing post-transplant CY is effective in in vivo TCD to promote full donor engraftment in patients with FA.


Subject(s)
Cyclophosphamide/administration & dosage , Fanconi Anemia/therapy , Lymphocyte Depletion/methods , Transplantation, Haploidentical/methods , Child , Child, Preschool , Drug Administration Schedule , Fanconi Anemia/mortality , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , T-Lymphocytes
2.
Mucosal Immunol ; 6(1): 69-82, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22739232

ABSTRACT

Influenza infection primarily targets the upper respiratory system, leading to a severe destruction of the epithelial cell layer. The role of immune cells in the regeneration of tracheal and bronchial epithelial cells is not well defined. Here, we investigated the production of pro-constructive cytokine, Interleukin-22 (IL-22), in the bronchoalveolar lavage (BAL), trachea, lung tissue, and spleen during influenza infection. We found that conventional natural killer (NK) cells (NCR1(+)NK1.1(+)CD127(-)RORγt(-)) were the predominant IL-22-producers in the BAL, trachea, and lung tissues. Tracheal epithelial cells constitutively expressed high levels of IL-22R and underwent active proliferation in response to IL-22 in the wild-type mice. Infection of IL-22(-/-) mice with influenza virus resulted in a severe impairment in the regeneration of tracheal epithelial cells. In addition, IL-22(-/-) mice continued to lose body weight even after 10 days post infection without any recovery. Tracheal epithelial cell proliferation was significantly reduced in IL-22(-/-) mice during influenza infection. Adoptive transfer of IL-22-sufficient but not IL-22-deficient NK cells into IL-22(-/-) mice restored the tracheal/bronchial epithelial cell regeneration and conferred protection against inflammation. Our findings strongly suggest that conventional NK cells have evolved to both kill virus-infected cells and also to provide vital cytokines for tissue regeneration.


Subject(s)
Inflammation/immunology , Inflammation/metabolism , Interleukins/biosynthesis , Killer Cells, Natural/immunology , Respiratory Mucosa/immunology , Respiratory Mucosa/metabolism , Adoptive Transfer , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , Cell Proliferation , Epithelial Cells/immunology , Epithelial Cells/metabolism , Epithelial Cells/virology , Humans , Inflammation/genetics , Interleukins/genetics , Killer Cells, Natural/cytology , Lung/immunology , Lung/metabolism , Mice , Natural Cytotoxicity Triggering Receptor 1/metabolism , Orthomyxoviridae/immunology , Orthomyxoviridae Infections/immunology , Regeneration , Respiratory Mucosa/pathology , Spleen/immunology , Spleen/metabolism , Trachea/immunology , Trachea/pathology , Trachea/virology , Interleukin-22
3.
Pediatr Hematol Oncol ; 29(6): 568-78, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22839094

ABSTRACT

Allogeneic hematopoietic cell transplantation (HCT) is the only known cure for patients with Fanconi anemia (FA) who develop aplasia or leukemia. However, transplant regimens typically contain high-dose alkylators, which are poorly tolerated in FA patients. Furthermore, as many patients lack human leukocyte antigen (HLA)-matched family donors, alternative donors are used, which can increase the risk of both graft rejection and graft-versus-host disease (GVHD). To improve on these three concerns, we developed a multi-institutional clinical trial using a fludarabine (FLU)-based conditioning regimen with limited alkylators/low-dose radiation, HLA-haploidentical marrow, followed by reduced-dose cyclophosphamide (CY) to treat three FA patients with aplasia. All three patients engrafted with 100% donor CD3 chimerism at 1 month. One patient died early from disseminated toxoplasmosis infection. Of the two survivors, one had significant pretransplant co-morbidities and inadequate immunosuppression, and developed severe acute GVHD. The other patient had only mild acute and no chronic GVHD. With a follow-up of 2 and 3 years, respectively, both patients are doing well, are transfusion-independent, and maintain full donor chimerism. The patient with severe GVHD has resolving oral GVHD and good quality of life. We conclude that using low-intensity conditioning, HLA-haploidentical marrow, and reduced-dose CY for in vivo T-cell depletion can correct life-threatening aplasia in FA patients.


Subject(s)
Fanconi Anemia/therapy , Graft Rejection/prevention & control , Graft vs Host Disease/prevention & control , HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation , Lymphocyte Depletion , T-Lymphocytes/immunology , Vidarabine/analogs & derivatives , Adolescent , Antineoplastic Agents/therapeutic use , Child , Combined Modality Therapy , Fanconi Anemia/immunology , Female , Follow-Up Studies , Humans , Transplantation Chimera/immunology , Transplantation Conditioning , Transplantation, Homologous , Vidarabine/therapeutic use
4.
Bone Marrow Transplant ; 46(4): 539-44, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20581880

ABSTRACT

A nonmyeloablative conditioning regimen consisting of fludarabine (FLU) and 2 Gy TBI has been used extensively and with substantial engraftment success without promoting excessive nonrelapse mortality in medically infirm patients requiring hematopoietic cell transplantation. In this paper, we studied this same low-toxicity regimen as a means of promoting engraftment of unrelated donor hematopoietic cell transplantation in patients with Fanconi anemia (FA). All patients tolerated the regimen well with no mucositis or other severe toxicities. Of six patients transplanted, five achieved stable mixed or full donor chimerism. Acute and chronic GVHD occurred in four and three patients, respectively. Three patients are alive and well at a median of 45.9 (range, 20.9-68.1) months after transplant. In summary, this FLU-based regimen facilitates stable engraftment of unrelated PBSCs, but is associated with significant chronic GVHD.


Subject(s)
Fanconi Anemia/therapy , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/adverse effects , Vidarabine/analogs & derivatives , Whole-Body Irradiation , Child , Fanconi Anemia/drug therapy , Female , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Survival Rate , Tissue Donors , Transplantation Chimera , Transplantation Conditioning/methods , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/toxicity , Whole-Body Irradiation/adverse effects
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