This project involves the conduct of therapeutic clinical trials for the treatment of inherited immune deficiencies using hematopoietic stem cell transplantation. We previously reported the successful use of non-ablative conditioning to achieve successful long-term engraftment and cure of CGD patients using HLA-matched sibling donors as the source of the hematopoietic stem cell graft. One of the problems with this approach was the high rate (30%) of graft failure or very low engraftment. In 2004 we performed a follow up transplant on an X-CGD child previously transplanted by us who had achieved high level donor T cell engraftment but less than 1% long term myeloid engraftment. We demonstrated successful permanent conversion to almost 100% donor chimerism in the lymphoid and myeloid lineages using single agent busulfan at 10 mg/kg as the conditioning. This strongly supports the use of this approach to rescue low engraftment rather than using a fully myelo- and lympho-ablative conditioning regimen for such salvage therapy. We have now opened a clinical trial to treat patients with immunodeficiencies using either a matched related, matched unrelated, or cord blood product and a tolerance inducing conditioning regimen consisting of Campath 1-H and busulfan with sirolimus for graft versus host disease (GvHD) prophylaxis. For patients receiving an unrelated product, total body irradiation is also added to the regimen. To date we have transplanted a total of 43 patients, 38 of whom received an unrelated donor graft. In patients not receiving a stem cell boost we have we have seen very limited GvHD with only one patient having Grade 2 skin GvHD and three patients with Grade 1 GvHD of the gut. We have used cord blood in 3 cases (two for CGD patients). One was for a patient with P67 deficient CGD and another with the X-linked form, both of whom failed to engraft. With the first CGD patient, the thinking was that the Campath impacted negatively with the ability of the more naive T cells in a cord blood graft preventing engraftment, and the protocol was modified to use ATG in the case of a cord blood product. However with the second graft failure in a CGD patient, we have stopped using cord blood products for these patients. This data is also correlated by results from Duke University where even with a myeloablative regimen, the engraftment rate using cord blood products in CGD patients is between 40 to 50%. The third patient to receive a cord blood graft was transplanted for X-linked Severe Combined Immunodeficiency. He was conditioned with ATG instead of Campath and is currently 7 years out with full engraftment, no evidence of graft versus host disease, and normal immune function. We now have had a total of nine deaths on the protocol with none in the last year. Two of the deaths were unrelated to the transplant (refusal to continue dialysis, and an accidental drug overdose). One patient developed a transfusion related acute lung injury after a platelet transfusion and three patients died from infection after developing GvHD (Klebsiella infection, adenovirus, and aspergillus brain abscess). One patient had pulmonary hemorrhage and CMV disease, and a final patient developed HHV6 after prolonged pancytopenia due to a late graft failure and despite a stem cell boost. Despite these outcomes, our overall mortality rate has been low relative to bone marrow transplantation in general using unrelated donors. Further we have transplanted a number of patients with ongoing infections including fungal osteomyelitis of the spine and/or meninges and in some cases have used granulocyte infusions during the period of transplant-induced neutropenia with no adverse effects. To date, all patients except one with CGD, transplanted with an ongoing infection have done well without any significant morbidity or mortality due to infection progression during the transplant course. Overall our results for the CGD patients in particular are especially promising with an overall survival of 38 out of 47 and an overall long term engraftment rate of 35 out of 38 evaluable. We are also the only centre to have transplanted patients with the P40 form of CGD demonstrating complete reversal of refractory colitis in this unique subset. (Manuscript in preparation.) In 2015 we have transplanted 4 XCGD patients to date with good results so far. At the end of 2014, we also initiated a clinical trial using haploidentical donors and transplanted a patient with no matched donors available (Protocol 15-I-0007). This patient had an ongoing infection refractory to all standard therapy and involving the heart as well as lungs and we therefore proceeded with a parental graft and post transplant cyclophosphamide. We obtained good engraftment with only limited graft versus host disease. This patient is doing well more than 9 months post transplant, and we now have a second patient currently undergoing transplant for an ongoing nocardia infection. If the results continue to be promising, we hope to expand the indication for haplotransplant to patients who are not necessarily actively infected. In order to determine the outcomes of transplant for CGD in general, we have become a part of the Primary Immune Deficiency Treatment Consortium and have initiated a collaborative protocol to review the results of transplant done for CGD in North America. The protocol has now been approved and is being implemented in various centers. Along with the clinical study, a substudy has also been initiated in collaboration with Emilia Falcone and Julie Segre, evaluating the microbiome in CGD patients and assessing the effects of transplant and/or colitis on the patients bacterial spectrum. We hope that this information may in fact be predictive for either development of colitis or GVHD leading to preventative treatments. In other related laboratory pre-clinical studies, we have been investigating the use of an adenosine A2a receptor agonist to prevent or treat graft versus host disease (GVHD). Prior studies have shown that agonists specific to this receptor improve outcomes in ischemia models of tissue damage. We have seen benefit in attenuating the onset and severity of GVHD in our F1-parental transplant model and have published this data in the Journal of Leukocyte Biology. Further studies have shown a role for T regulatory cells (Tregs) as part of the mechanism of the drugs effects. We have now established a new CRADA with Lewis and Clark Pharmaceuticals (formally Adenosine Therapeutics/PgxHealth/Forest Labs) to study other formulations of the A2a receptor agonists and have seen similar effects on T regs, both invitro and invivo, by these agonists. This data was published in the Journal of Immunology and we recently published a review paper regarding the use adenosine agonists in GVHD. Dr Sharma a postdoctoral fellow who joined the lab in January was the first author. Moreover, we have started to study these drugs in a colitis model given their benefit in GvHD of the gut. We have also continued our collaboration with Gabriel Dvesklar of UHSUS to study Pregnancy Specific Glycoprotein -1 (PSG-1) as an immunomodulator and a possible therapy for GvHD. Preliminary in vitro and in vivo studies have been promising with reduced GvHD seen in our mouse models treated with the protein. Dr Sharma has submitted an abstract to present some of this data at the annual American Society of Hematology meeting.

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Jones, Karlie R; Choi, Uimook; Gao, Ji-Liang et al. (2017) A Novel Method for Screening Adenosine Receptor Specific Agonists for Use in Adenosine Drug Development. Sci Rep 7:44816
Parta, Mark; Kelly, Corin; Kwatemaa, Nana et al. (2017) Allogeneic Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: a Single-Center Prospective Trial. J Clin Immunol 37:548-558
Kuhns, Douglas B; Fink, Danielle L; Choi, Uimook et al. (2016) Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency. Blood 128:2135-2143
Jones, Karlie; Ballesteros, Angela; Mentink-Kane, Margaret et al. (2016) PSG9 Stimulates Increase in FoxP3+ Regulatory T-Cells through the TGF-?1 Pathway. PLoS One 11:e0158050
De Ravin, Suk See; Wu, Xiaolin; Moir, Susan et al. (2016) Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med 8:335ra57
Panch, Sandhya R; Yau, Yu Ying; Kang, Elizabeth M et al. (2015) Mobilization characteristics and strategies to improve hematopoietic progenitor cell mobilization and collection in patients with chronic granulomatous disease and severe combined immunodeficiency. Transfusion 55:265-74
Parta, Mark; Hilligoss, Dianne; Kelly, Corin et al. (2015) Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in a Patient with Chronic Granulomatous Disease and Active Infection: A First Report. J Clin Immunol 35:675-80
Jones, Karlie R; Kang, Elizabeth M (2015) Graft versus host disease: New insights into A2A receptor agonist therapy. Comput Struct Biotechnol J 13:101-5
Marciano, Beatriz E; Spalding, Christine; Fitzgerald, Alan et al. (2015) Common severe infections in chronic granulomatous disease. Clin Infect Dis 60:1176-83
Elinoff, Jason M; Bagci, Ulas; Moriyama, Brad et al. (2014) Recombinant human factor VIIa for alveolar hemorrhage following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 20:969-78

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