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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

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.

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

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

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...

Biology of Blood and Marrow Transplantation, 2016

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.

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.

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.

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.

Clinical Infectious Diseases, 2011

Blood Cells, Molecules, and Diseases, 2008

Blood, 2014

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