Dianne Hilligoss - Profile on Academia.edu (original) (raw)

Peer-reviewed articles by Dianne Hilligoss

WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal domina... more WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal dominant mutations truncating the C-terminus of the chemokine receptor CXCR4. WHIM mutations may potentiate CXCR4 signaling, suggesting that the FDA-approved CXCR4 antagonist AMD3100 (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing CHO and K562 cell lines matched for expression of recombinant wild type CXCR4 (CXCR4(WT) ) and the most common WHIM variant of CXCR4 (CXCR4(R334X) ), as well as leukocytes from a WHIM patient with the CXCR4(R334X) mutation versus healthy controls. We found that CXCR4(R334X) mediated modestly increased signaling (∼2-fold) in all functional assays tested, but strongly resisted ligand-dependent downregulation. AMD3100 was equipotent and equieffective as an antagonist at CXCR4(R334X) and CXCR4(WT) . Together, our data provide further evidence that CXCR4(R334X) is a gain-of-function mutation, and support clinical evaluation of AMD3100 as mechanism-based treatment in patients with WHIM syndrome.

Papers by Dianne Hilligoss

AMD3100 is a potent antagonist at CXCR4R334X, a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome

Journal of Cellular and Molecular Medicine, 2011

WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal domina... more WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal dominant mutations truncating the C‐terminus of the chemokine receptor CXC chemokine receptor 4 (CXCR4). WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)‐approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing Chinese hamster ovary (CHO) and K562 cell lines matched for expression of recombinant wild‐type CXCR4 (CXCR4WT) and the most common WHIM variant of CXCR4 (CXCR4R334X), as well as leucocytes from a WHIM patient with the CXCR4R334X mutation versus healthy controls. We found that CXCR4R334X mediated modestly increased signalling (∼2‐fold) in all functional assays tested, but strongly resisted ligand‐dependent down‐regulation. AMD3100 was equipotent and equieffective as an antagonist at CXCR4R334X and CXCR4WT. Tog...

The Use Of a Novel Nonmyeloablative Conditioning Regimen and Sirolimus For GvHD Prophylaxis To Transplant Patients With Chronic Granulomatous Disease

Blood, Nov 15, 2013

Chronic Granulomatous Disease (CGD) results from a mutation in the NADPH oxidase complex. As a re... more Chronic Granulomatous Disease (CGD) results from a mutation in the NADPH oxidase complex. As a result, patients are prone to recurrent infections and an increased risk of autoimmune disorders such as colitis. Currently, the only available cure is hematopoietic stem cell transplantation using a related or unrelated donor. In 2002, the NIH published their results using a nonmyeloablative regimen and sibling matched donors. Although the results were overall promising, there was still significant GvHD in older patients and a number of graft rejections in the younger patients. Further accrual was limited due to donor unavailability. In 2007, after establishing an agreement with the National Marrow Donor Program, we were able to initiate a protocol for patients with primary immunodeficiencies using an HLA matched unrelated donor. The goal of this protocol was to achieve engraftment in patients with CGD, including high risk patients due to the presence of an ongoing infection or inflammation, without increasing the rate of graft versus host disease. We therefore devised a novel conditioning regimen of Busulfan, Campath, and TBI along with sirolimus as the sole GVHD prophylaxis. To date we have transplanted 21 evaluable patients. Results are summarized below:AgeInfectionInflammationaGvHDcGvHDadditional cells?A&amp;amp;Wcause of death32XX1Nrefused dialysis25XGrade 1Y21XXGrade 1Y19X (colostomy)Grade 4XNinfection, GvHD of skin17XX2NEvan&#39;s/TRALI/GvHD17XNpulmonary hemorrhage17XGrade 2Y12XlimitedXY7XY8XY8X (colostomy)Grade 1Y8XXY6XX3NGvHD after 3rd transplant5XY4XY4XXGrade 2Y17Y11Grade 1Y10Y10Y8Y 1. Received peripheral blood stem cells from same donor after receiving bone marrow 2. Received cells after additional conditioning in the setting of Evan’s syndrome 3. Received additional cells with initial graft failure. Went on to a second then third transplant with a different conditioning regimen and different donor. Overall survival was 76%; however all deaths occurred in high risk patients and 2 of the 5 were unrelated to the initial transplant. Further, all surviving patients transplanted with high risk disease (11 of the 16) continue to have stable engraftment and had complete resolution of their inflammation and/or infection. This includes a patient with P40phox deficiency whose primary manifestation of CGD was colitis as well as a patient with an invasive fungal infection requiring emergency laminectomy 3 weeks prior to transplant. We have had limited GvHD to date and this occurred primarily in the high risk patients (6 of the 7). The most severe GvHD occurred in a patient given additional cells due possible poor engraftment and persistent thrombocytopenia. In retrospect, this may have been a sign of GvHD and not graft failure; however the result was severe GvHD of the skin and ultimately death from sepsis. Further, the only chronic GvHD (transient, now resolved) was also in a patient given additional cells for concerns of possible graft failure. Subsequently, the protocol was modified to no longer give additional unmanipulated cells and no graft failures or any severe GvHD has occurred in any of the subsequent patients. In general, patients tolerated the transplant well, although we did see a higher than expected rate of engraftment syndrome, again in the high risk patients only (5 of 21). Many patients needed only 1 or 2 transfusions of either platelets or red blood cells and 3 did not require any transfusions at all. We also transplanted two patients with CGD/McLeod’s, banking autologous blood prior to the transplant, and only one patient required any blood (1 autologous unit). Three patients did require multiple infusions due to prolonged time to engraftment or slow platelet recovery including the one patient to receive bone marrow as their initial donor product. For the one patient with late graft failure, there was autologous recovery. Thus in this single centre study we have transplanted 21 patients to date including 16 of those considered high risk using a novel non-myeloablative transplant regimen and an unrelated donor. We have had significantly lower rates of GvHD (33%) of which &amp;lt;10% was greater than Grade 2 and only one patient with graft failure. Overall, the combination of Campath and Sirolimus, along with Busulfan and low dose radiation is well tolerated and has a low risk of graft versus host disease while still allowing engraftment in patients, even those with high risk disease. Disclosures: No relevant conflicts of interest to declare.

Biology of Blood and Marrow Transplantation, Feb 1, 2011

Journal of Clinical Immunology, Apr 20, 2020

serostatus, female-into-male allografting, remission status at alloBMT, allograft total nucleated... more serostatus, female-into-male allografting, remission status at alloBMT, allograft total nucleated cell count, allograft CD34 + cell count, and cohort (HLA-matched versus HLAhaploidentical) as covariates [Table ]. At 2 months posttransplant, these four biomarkers remained predictive of non-relapse mortality events occurring after that time point (not shown). Conclusion: Four proteomic biomarkers previously explored using other alloBMT platforms are predictive of NRM when using PTCy-based alloBMT platforms, including using HLAhaploidentical or HLA-matched-related or eunrelated donors. These biomarkers may be useful in guiding treatment decisions and directing more intensive monitoring of patients at high-risk for poor outcomes.

Journal of Clinical Immunology, Oct 1, 2015

Purpose-We describe haploidentical hematopoietic cell transplantation (HCT) with high-dose post-t... more Purpose-We describe haploidentical hematopoietic cell transplantation (HCT) with high-dose post-transplant cyclophosphamide (PTCy) in a boy with x-linked chronic granulomatous disease (CGD). Methods-A persistent and life-threatening fungal infection was the indication for HSCT. Nonmyeloablative conditioning with PTCy (50 mg/kg days 3 and 4) was used in the absence of fully matched donors. Results-Engraftment occurred on day 24. The patient experienced Grade 2 graft-versus-host disease of the skin and gastrointestinal tract and CMV infection, both of which were controlled. Chimerism was 100 % at days 30 and 6 months. Cessation of antifungal therapy was consistent with cure of the infection. Conclusions-Haploidentical HCT with high-dose PTCy for CGD is feasible and succeeded even in the context of active infection.

Allogeneic Transplantation for P40 CGD Is Curative of Inflammatory Disease

Blood, 2015

Chronic Granulomatous Disease is an inherited immunodeficiency resulting from a defect in one of ... more Chronic Granulomatous Disease is an inherited immunodeficiency resulting from a defect in one of 5 proteins necessary for the production of NADPH oxidase, an important component in managing infections by neutrophils. The most common form of the disease is X-linked due to mutations in the GP91 protein. Patients with CGD are thus prone to various infections from specific bacteria and/or fungi, but generally have normal viral responses. They are also prone to inflammatory diseases, including sarcoid, lupus, and colitis. Allogeneic hematopoieitic transplantation has been shown to be curative and will arrest or even reverse some of the inflammatory problems and is now more commonly used in patients with a history of inflammation or recurrent infections. In 2009, a new form of CGD was described resulting from a mutation in the P40 protein and to date only 2 patients have been described with this form of CGD. Unlike the other subtypes, these patients did not present with infection but in f...

Journal of Clinical Immunology, 2020

Purpose Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chr... more Purpose Haploidentical related donor (HRD) transplantation was performed in 7 recipients with chronic granulomatous disease (CGD) who had no matched-related or unrelated donor. Methods Peripheral blood cell (PBC) products were used with a conditioning regimen consisting of low-dose cyclophosphamide, fludarabine, total body irradiation, and busulfan. Graft-versus-host disease (GVHD) prophylaxis consisted of high-dose posttransplant cyclophosphamide and sirolimus. Recipients were ages 14-26 years, and 3 had severe infections active at transplant. Results All 7 recipients achieved full engraftment with complete donor chimerism early in the post-transplant period. Acute GVHD occurred in all cases and was grade 3 or steroid refractory in 3. Two patients with steroid-refractory GVHD died. Three patients with severe infectious complications active at transplant, 1 Nocardia pneumonia and 2 extensive invasive fungal infections), survived and were cured of their infection at last follow-up. Bacterial disease occurred post-transplant in all recipients, and viral infections/reactivation were common, including 4 cases of BK virus-associated hemorrhagic cystitis. Conclusions Seven patients with CGD achieved rapid and full-donor engraftment from HRDs utilizing PBCs and a conditioning regimen with PTCy and sirolimus GVHD prophylaxis. However, the incidence of grade 3 and steroid-refractory GVHD was high and led to 2 deaths. Patients with active infections at transplant had successful transplant courses and were cured of their disease. Although there was an initial success with this regimen, the cumulative experience does not support its use in CGD due to an unacceptable rate of severe GVHD.

Biology of Blood and Marrow Transplantation, 2019

Bone marrow was the graft source in 73.7%. Unrelated donors were employed in 41 (51%) cases, 61% ... more Bone marrow was the graft source in 73.7%. Unrelated donors were employed in 41 (51%) cases, 61% of whom with. Non-m, while 41% and 9% received a fully myeloablative and a reduced-intense regimen, respectively. Acute and chronic GvHD occurred in 38.7% and 28.7% of patients, respectively. Chimerism analysis were performed by short tandem repeat (STR) on DNA extracted from whole peripheral blood (WB) and CD3+, CD19+ and CD34+ leukocyte subsets, at 30 days (D+30), 100 days (D+100), 6 months and 1-year post-HSCT. was available in 71 patients: it was a mixed chimerism (<95%) in 12, complete donor chimerism in 53 (46 with whole blood chimerism between 95 and 99.99%) and no donor chimerism in six patients. Secondary graft failure occurred in seven patients at a median time of 52 days after HSCT (range, 22-1513 days). Of these seven patients, the D+30 donor chimerism was mixed on WB in three, mixed on CD3 in five and zero in two patients, respectively. The cumulative incidence of grade II-IV acute GvHD was associated with a full donor chimerism in WB at D+30 (p = 0.01), while chronic GvHD was higher in patients experiencing full donor chimerism either in WB and CD3+ at D+100 (p = 0.02). One-year overall survival was 81.2% and was not affected by chimerism status. Conclusion: Chimerism kinetic performed on sorted populations at different time points post allo-HSCT can predict outcomes in non-malignant disorders. Based on our preliminary results, D+30, D+100 and the chimerism on CD3+ are informative and should be monitored carefully in patients with nonmalignant disorders.

Journal of Allergy and Clinical Immunology, 2008

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma format... more Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune (AI) disorders. In this report, we describe antiphospholipid syndrome (aPL), recurrent pericardial effusion, juvenile idiopathic arthritis (JIA), IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease has important treatment implications for patients with CGD.

Pulmonary Nontuberculous Mycobacterial Disease

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

Science translational medicine, Jan 20, 2016

X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural... more X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been ac...

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for High Risk Chronic Granulomatous Disease (CGD) Patients

Biology of Blood and Marrow Transplantation, 2016

Severe congenital neutropenia due to G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis

Blood, 2010

Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in a Patient with Chronic Granulomatous Disease and Active Infection: A First Report

Journal of Clinical Immunology, 2015

We describe haploidentical hematopoietic cell transplantation (HCT) with high-dose post-transplan... more We describe haploidentical hematopoietic cell transplantation (HCT) with high-dose post-transplant cyclophosphamide (PTCy) in a boy with x-linked chronic granulomatous disease (CGD). A persistent and life-threatening fungal infection was the indication for HSCT. Non-myeloablative conditioning with PTCy (50 mg/kg days 3 and 4) was used in the absence of fully matched donors. Engraftment occurred on day 24. The patient experienced Grade 2 graft-versus-host disease of the skin and gastrointestinal tract and CMV infection, both of which were controlled. Chimerism was 100 % at days 30 and 6 months. Cessation of antifungal therapy was consistent with cure of the infection. Haploidentical HCT with high-dose PTCy for CGD is feasible and succeeded even in the context of active infection.

PEDIATRICS, 2004

Objective. Chronic granulomatous disease (CGD) is a rare disorder of phagocyte oxidative metaboli... more Objective. Chronic granulomatous disease (CGD) is a rare disorder of phagocyte oxidative metabolism. In addition to infectious complications, granulomatous lesions often involve hollow viscera, especially the gastrointestinal (GI) tract. The objective of this study was to evaluate the clinical presentation, prevalence, and consequences of GI involvement in patients with CGD.

Abstract No. 313: Pasteurization of hepatic abscesses with RFA in immunocompromised patients with chronic granulomatous disease

Journal of Vascular and Interventional Radiology, 2011

Journal of Allergy and Clinical Immunology, 2009

message: Serratia marcescens infections that occur in older children and adults with chronic gran... more message: Serratia marcescens infections that occur in older children and adults with chronic granulomatous disease have a pattern different from that seen in infants with CGD in that osteomyelitis is much less common; skin infections form large poorly healing ulcers; and infections frequently occur in a metastatic fashion at multiple sites including cryptic internal sites.

Hepatic abnormalities in patients with chronic granulomatous disease

Hepatology, 2007

Chronic granulomatous disease (CGD) is a rare congenital disorder characterized by repeated bacte... more Chronic granulomatous disease (CGD) is a rare congenital disorder characterized by repeated bacterial and fungal infections. Aside from a high incidence of liver abscess, little is known about hepatic involvement in CGD. The aim of this study was to describe the spectrum of liver abnormalities seen in CGD. The charts of 194 patients with CGD followed at the NIH were reviewed, with a focus on liver abnormalities. Liver enzyme elevations occurred on at least one occasion in 73% of patients during a mean of 8.9 years of follow-up. ALT elevations were generally transient. Although transient alkaline phosphatase (ALP) elevations were also common, persistent ALP elevations lasting up to 17.6 years were seen in 25% of patients. Liver abscess occurred in 35% of patients. Drug-induced hepatotoxicity was documented in 15% of patients but likely occurred more frequently. Hepatomegaly was found in 34% and splenomegaly in 56% of patients. Liver histology showed granulomata in 75% and lobular hepatitis in 90% of specimens. Venopathy of the portal vein was common (80%) and associated with splenomegaly. Venopathy of the central vein was also common (63%) and was associated with the number of abscess episodes. Nodular regenerative hyperplasia (NRH) was seen in 9 patients, including 6 of 12 autopsy specimens. Liver enzyme abnormalities occur frequently in patients with CGD. In addition to liver abscesses and granulomata, drug hepatotoxicity is likely underappreciated. Vascular lesions such as venopathy and--to a lesser extent--NRH are common. The cause and clinical consequences of venopathy await prospective evaluation.

AMD3100 is a potent antagonist at CXCR4R334X, a hyperfunctional mutant chemokine receptor and cause of WHIM syndrome

Journal of Cellular and Molecular Medicine, 2011

WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal domina... more WHIM is an acronym for a rare immunodeficiency syndrome (OMIM #193670) caused by autosomal dominant mutations truncating the C‐terminus of the chemokine receptor CXC chemokine receptor 4 (CXCR4). WHIM mutations may potentiate CXCR4 signalling, suggesting that the United States Food and Drug Administration (FDA)‐approved CXCR4 antagonist AnorMED3100 (AMD3100) (also known as Plerixafor) may be beneficial in WHIM syndrome. We have tested this at the preclinical level by comparing Chinese hamster ovary (CHO) and K562 cell lines matched for expression of recombinant wild‐type CXCR4 (CXCR4WT) and the most common WHIM variant of CXCR4 (CXCR4R334X), as well as leucocytes from a WHIM patient with the CXCR4R334X mutation versus healthy controls. We found that CXCR4R334X mediated modestly increased signalling (∼2‐fold) in all functional assays tested, but strongly resisted ligand‐dependent down‐regulation. AMD3100 was equipotent and equieffective as an antagonist at CXCR4R334X and CXCR4WT. Tog...

The Use Of a Novel Nonmyeloablative Conditioning Regimen and Sirolimus For GvHD Prophylaxis To Transplant Patients With Chronic Granulomatous Disease

Blood, Nov 15, 2013

Biology of Blood and Marrow Transplantation, Feb 1, 2011

Journal of Clinical Immunology, Apr 20, 2020

Journal of Clinical Immunology, Oct 1, 2015

Allogeneic Transplantation for P40 CGD Is Curative of Inflammatory Disease

Blood, 2015

Journal of Clinical Immunology, 2020

Biology of Blood and Marrow Transplantation, 2019

Journal of Allergy and Clinical Immunology, 2008

Pulmonary Nontuberculous Mycobacterial Disease

American Journal of Respiratory and Critical Care Medicine, Dec 20, 2012

Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency

Science translational medicine, Jan 20, 2016

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for High Risk Chronic Granulomatous Disease (CGD) Patients

Biology of Blood and Marrow Transplantation, 2016

Severe congenital neutropenia due to G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis

Blood, 2010

Haploidentical Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide in a Patient with Chronic Granulomatous Disease and Active Infection: A First Report

Journal of Clinical Immunology, 2015

PEDIATRICS, 2004

Abstract No. 313: Pasteurization of hepatic abscesses with RFA in immunocompromised patients with chronic granulomatous disease

Journal of Vascular and Interventional Radiology, 2011

Journal of Allergy and Clinical Immunology, 2009

Hepatic abnormalities in patients with chronic granulomatous disease

Hepatology, 2007

Gastroenterology, 2008

Background-Chronic granulomatous disease (CGD) is a rare genetic disorder, predisposing affected ... more Background-Chronic granulomatous disease (CGD) is a rare genetic disorder, predisposing affected individuals to recurrent infectious complications and reduced survival. Liver involvement in CGD includes vascular abnormalities, which may lead to non-cirrhotic portal hypertension.