Hematopoietic stem cell transplantation for RelB deficiency

Abstract

The nuclear factor kappa B (NF-κB) family of transcription factors regulates diverse biological processes, including innate and adaptive immunity, stress responses, apoptosis, and differentiation.1Hayden M.S. Ghosh S. NF-kappaB in immunobiology.Cell Res. 2011; 21: 223-244Crossref PubMed Scopus (636) Google Scholar, 2Kawai T. Nishikomori R. Heike T. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency.Allergol Int. 2012; 61: 207-217Abstract Full Text PDF PubMed Scopus (41) Google Scholar The NF-κB family includes the structurally homologous transcription factors NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA (p65), RelB, and c-Rel that interact to form homodimers and heterodimers with distinct gene regulatory functions.3Paciolla M. Pescatore A. Conte M.I. Esposito E. Incoronato M. Lioi M.B. et al.Rare Mendelian primary immunodeficiency diseases associated with impaired NF-kappaB signaling.Genes Immun. 2015; 16: 239-246Crossref PubMed Scopus (25) Google Scholar NF-κB dimers are inactive in the cytosol, retained in a latent state through interaction with inhibitor of NF-κB proteins (IκBs).4Sun S.C. The noncanonical NF-kappaB pathway.Immunol Rev. 2012; 246: 125-140Crossref PubMed Scopus (505) Google Scholar The release of NF-κB dimers from IκB proteins is dependent on activation of the IκB kinase (IKK) complex.3Paciolla M. Pescatore A. Conte M.I. Esposito E. Incoronato M. Lioi M.B. et al.Rare Mendelian primary immunodeficiency diseases associated with impaired NF-kappaB signaling.Genes Immun. 2015; 16: 239-246Crossref PubMed Scopus (25) Google Scholar Two NF-κB pathways are recognized, the classical, mediated by RelA (and c-Rel), and the alternative, mediated by RelB.5Sharfe N. Merico D. Karanxha A. Macdonald C. Dadi H. Ngan B. et al.The effects of RelB deficiency on lymphocyte development and function.J Autoimmun. 2015; 65: 90-100Crossref PubMed Scopus (43) Google Scholar The canonical pathway responds to antigen receptors, cytokine receptors, and pattern recognition receptors,4Sun S.C. The noncanonical NF-kappaB pathway.Immunol Rev. 2012; 246: 125-140Crossref PubMed Scopus (505) Google Scholar and on receptor activation, the IKK complex phosphorylates IκBα, leading to the nuclear translocation of p50/RelA and p50/c-Rel dimers. Activation of the noncanonical NF-κB pathway is triggered by other receptors including BaffR and CD40, and leads to processing of the NF-κB2 precursor protein, p100, and subsequent activation of the p52/RelB dimer.4Sun S.C. The noncanonical NF-kappaB pathway.Immunol Rev. 2012; 246: 125-140Crossref PubMed Scopus (505) Google Scholar Deleterious mutations in genes encoding various components of the NF-κB pathway, such as mutations in IKK-γ, IκBα, and inhibitor of NF-κB kinase subunit beta IKKβ (IKK2) and NF-κB1 or RelB, lead to a spectrum of combined immunodeficiencies with various severity.3Paciolla M. Pescatore A. Conte M.I. Esposito E. Incoronato M. Lioi M.B. et al.Rare Mendelian primary immunodeficiency diseases associated with impaired NF-kappaB signaling.Genes Immun. 2015; 16: 239-246Crossref PubMed Scopus (25) Google Scholar, 5Sharfe N. Merico D. Karanxha A. Macdonald C. Dadi H. Ngan B. et al.The effects of RelB deficiency on lymphocyte development and function.J Autoimmun. 2015; 65: 90-100Crossref PubMed Scopus (43) Google Scholar, 6Merico D. Sharfe N. Hu P. Herbrick J.-A. Roifman C.M. RelB deficiency causes combined immunodeficiency.LymphoSign J. 2015; 2: 147-155Crossref Google Scholar Patients may also exhibit other features such as ectodermal dysplasia.3Paciolla M. Pescatore A. Conte M.I. Esposito E. Incoronato M. Lioi M.B. et al.Rare Mendelian primary immunodeficiency diseases associated with impaired NF-kappaB signaling.Genes Immun. 2015; 16: 239-246Crossref PubMed Scopus (25) Google Scholar The role of the noncanonical pathway in immunity was believed to be limited to transmitting signals downstream of only a few receptors, as compared with the classical pathway. It was therefore surprising that defects in this pathway resulted in equally significant immunodeficiencies. Heterozygous mutations in NF-κB2 were found to be associated with common variable immunodeficiency, and were indistinguishable from defects in NF-κB1. More recently, RelB deficiency was identified in patients with repeated infections, failure to thrive, and autoimmunity.5Sharfe N. Merico D. Karanxha A. Macdonald C. Dadi H. Ngan B. et al.The effects of RelB deficiency on lymphocyte development and function.J Autoimmun. 2015; 65: 90-100Crossref PubMed Scopus (43) Google Scholar They were found to have a homozygous c.C1191A/p.Y397X mutation that creates a premature stop codon, which blocked translation of the last 3 exons.6Merico D. Sharfe N. Hu P. Herbrick J.-A. Roifman C.M. RelB deficiency causes combined immunodeficiency.LymphoSign J. 2015; 2: 147-155Crossref Google Scholar Although the number of circulating lymphocytes was normal, the lack of T-cell responses to mitogens, low levels of T-cell receptor excision circles (TRECs), and the finding of a dysplastic thymus all supported the diagnosis of a profound T-cell immunodeficiency.5Sharfe N. Merico D. Karanxha A. Macdonald C. Dadi H. Ngan B. et al.The effects of RelB deficiency on lymphocyte development and function.J Autoimmun. 2015; 65: 90-100Crossref PubMed Scopus (43) Google Scholar Treatment options in these conditions usually involve immunoglobulin replacement and early empirical antibiotic treatment for antibody deficiency and infections. However, profound T-cell dysfunction observed in some patients has encouraged more radical solutions such as hematopoietic stem cell transplantation (HSCT), which has been tried infrequently with contrasting results.2Kawai T. Nishikomori R. Heike T. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency.Allergol Int. 2012; 61: 207-217Abstract Full Text PDF PubMed Scopus (41) Google Scholar We report here, for the first time, the course and outcome of HSCT in 2 patients with RelB deficiency. Patient 1 suffered repeated respiratory infections including multiple episodes of pneumonia, herpes simplex virus-1 skin infection, arthritis, ecthyma gangrenosum, and failure to thrive.5Sharfe N. Merico D. Karanxha A. Macdonald C. Dadi H. Ngan B. et al.The effects of RelB deficiency on lymphocyte development and function.J Autoimmun. 2015; 65: 90-100Crossref PubMed Scopus (43) Google Scholar At the age of 1 year, he underwent HSCT from a 10/10 HLA-matched unrelated donor. He received myeloablative conditioning regimen consisting of busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). Graft versus host disease (GvHD) prophylaxis consisted of cyclosporine A (target levels, 175-200 mg/L) and methylprednisolone (2 mg/kg). The patient tolerated the conditioning with no complications. Neutrophil engraftment occurred +18 days post-HSCT. He developed grade I acute skin GvHD at +13 days post-HSCT, which resolved with a pulse of high dose of methylprednisolone (30 mg/kg) and suffered HSV1 stomatitis at +42 days post-HSCT, which was controlled with intravenous acyclovir. Both immunosuppression and intravenous immunoglobulin replacement were discontinued 10 months after transplant; however, 8 months later his arthritis returned and involved both wrists, ankles, knees, and the left hip. He was treated with naproxen as well as corticosteroid joint injections, with full resolution of symptoms. Concomitantly, he developed patches of flat, brown-colored skin discolouration on the neck (Fig 1, A), chest, and buttocks. A skin biopsy showed ashy dermatosis (Fig 1, B-F), which appears to occur in patients with immune dysregulation. These lesions almost completely resolved after topical corticosteroid treatment. Six months later, he developed bound down plaques predominately on his lower abdomen and thighs, consistent with chronic GvHD. Methotrexate injections arrested progression and improved the skin changes. It remains unclear whether the episode of ashy dermatosis was an independent, distinct autoimmune manifestation like the arthritis, or rather a precursor to chronic GvHD. Equally interesting is the question of whether some of these manifestations may be related or aggravated by a possible sluggish rehabilitation of the RelB-deficient thymus posttransplantation. Currently, the patient is clinically well, attending school, growing, and gaining weight. Evaluation of engraftment consistently demonstrated more than 95% donor T and B cells, monocytes, and neutrophils. Immune reconstitution in spite of immunosuppression was solid, revealing normal mitogenic responses to PHA and anti-CD3, as well as to tetanus toxoid and herpes simplex antigens (Table I). T-cell receptor repertoire appeared to include all T-cell receptor Vβ family groups, consistent with polyclonal reconstitution (Fig 1, G); however, TREC levels remain depressed. Immunoglobulin levels and specific antibody formation in response to vaccination were normal.Table IImmune function of the RelB-deficient patients after HSCTCharacteristicPatient 1Patient 2Normal rangeAge (y)65.5NATime post-BMT (y)53.5NAImmunophenotyping (cells/μL) CD310031168700-4200 CD4731668300-2000 CD8292481300-1800 CD19/202208901200-1600 CD5643220590-900Mitogen responses (stimulation index; % of control) PHA9075>50% Anti-CD35860>50%Antigen responses (stimulation index) Herpes simplex105<20>20 Tetanus toxoid3098>20TRECs (copies/μg)51718>400Immunoglobulins (g/L) IgG7.77.95.0-14.6 IgA0.70.80.3-2.0 IgM0.30.30.2-2.5Antitetanus (IU/mL)1.230.7>0.1BMT, Bone marrow transplant; NA, not applicable. Open table in a new tab BMT, Bone marrow transplant; NA, not applicable. Similar to his cousin, patient 2 suffered repeated episodes of pneumonia since infancy and failure to thrive.5Sharfe N. Merico D. Karanxha A. Macdonald C. Dadi H. Ngan B. et al.The effects of RelB deficiency on lymphocyte development and function.J Autoimmun. 2015; 65: 90-100Crossref PubMed Scopus (43) Google Scholar At the age of 2 years, he underwent HSCT from a 10/10 HLA-matched unrelated donor after receiving a similar regimen of myeloablative conditioning and GvHD prophylaxis. His posttransplant course was uneventful, allowing for a quick (<6 months) cessation of immunosuppression and intravenous immunoglobulin replacement. Assessment of engraftment at 3 years posttransplant showed mixed chimerism with 40% of T cells and 13% of B cells being of donor origin, whereas neutrophils remained mostly of recipient origin. In spite of the mixed chimerism, immune reconstitution appeared solid with normal in vitro responses to mitogens, antigens, and normal TREC levels. Immunoglobulin and specific antibody levels were also within normal limits. He is currently growing and developing well, with no signs of GvHD or other complications at 3.5 years after transplant. The outcome of HSCT in patients with NF-κB defects is inconsistent, and the reason for these variations is hard to decipher because many determinants such as age of transplant, pretransplant morbidities, conditioning regimens, stem cell sources, and posttransplant management differ widely among HSCT recipients. Posttransplant challenges including hepatotoxicity, poor engraftment, and partial immune reconstitution, as well as failure to resolve preexisting autoimmune manifestations like colitis were reported.7Chen K. Coonrod E.M. Kumanovics A. Franks Z.F. Durtschi J.D. Margraf R.L. et al.Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency.Am J Hum Genet. 2013; 93: 812-824Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 8Chandrakasan S. Marsh R.A. Uzel G. Holland S.M. Shah K.N. Bleesing J. Outcome of patients with NEMO deficiency following allogeneic hematopoietic cell transplant.J Allergy Clin Immunol. 2017; 139: 1040-1043.e2Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar, 9Pai S.Y. Levy O. Jabara H.H. Glickman J.N. Stoler-Barak L. Sachs J. et al.Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-kappaB essential modulator deficiency.J Allergy Clin Immunol. 2008; 122: 1113-1118.e1Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar We have not observed hepatotoxicity in our patients, but the persistence of arthritis in patient 1 is consistent with experience with NF-κB defects. The mixed chimerism observed in patient 2 is rare and occurred in less than 3% of patients in our centre receiving full myeloablative conditioning for severe combined immunodeficiency or combined immunodeficiency. All previous cases occurred before the era of closely monitoring busulfan levels. This finding may be reminiscent of experience with HSCT for NF-κB defects. Yet, the gradual improvement in all parameters of immune function, clinical well-being, excellent ability to fight infections, and the sustained chimerism for more than 3.5 years make the possibility of an eventual graft loss unlikely. Indeed, mixed chimerism observed in other NF-κB defects persisted for at least a decade posttransplant (see Table E1 in this article's Online Repository at www.jacionline.org). In conclusion, we have shown that a myeloablative regimen, which is required in cases in which engraftment may be challenging, is safe for RelB-deficient patients. The transplant procedure and course were also uneventful in both patients. Engraftment was complete and remained solid for over 5 years in patient 1, but partial, yet sustained in the other. Still, immune reconstitution is robust for both cellular and humoral immunity, and growth and development, resistance to infections, and quality of life have all improved, and are comparable to healthy children. Together with the cases reported here, the overall survival of patients with NF-κB defects after HSCT is 70%, which should encourage future attempts to perform the procedure and improve outcomes in cases with severe T-cell deficiencies. Table E1Outcome of HSCT in NF-κB defectsCaseMutationAge of HSCTHLA matchSourceConditioningGvHD prophylaxisSecond HSCT or boostGvHDGraft/chimerismOutcomeFollow-up duration (y)Reference1RelB2 yMUD10/10BMBu/CyCSA,MPDGrade ISkin GvHDChronic GvHD skinAlive52RelB3 yMUD10/10BMBu/CyCSA,MPDMixed chimerismAlive3.53NEMO 1167insC3 y 4 moMUD8/8CBBu/Cy/ATGCSA, prednisoneChronic skin GvHDAlive9E1Chandrakasan S. Marsh R.A. Uzel G. Holland S.M. Shah K.N. Bleesing J. Outcome of patients with NEMO deficiency following allogeneic hematopoietic cell transplant.J Allergy Clin Immunol. 2017; 139: 1040-1043Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar4NEMO R254Q7 y 9 moMUD8/8CBBU/CY/ATGCSA, prednisoneStem cell boostGrade IIskin and liverMixed chimerismAlive9E1Chandrakasan S. Marsh R.A. Uzel G. Holland S.M. Shah K.N. Bleesing J. Outcome of patients with NEMO deficiency following allogeneic hematopoietic cell transplant.J Allergy Clin Immunol. 2017; 139: 1040-1043Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar5NEMO M407V13 y 6 moMUD7/8CBBU/CY/ATGCSA, prednisoneAlive9E1Chandrakasan S. Marsh R.A. Uzel G. Holland S.M. Shah K.N. Bleesing J. Outcome of patients with NEMO deficiency following allogeneic hematopoietic cell transplant.J Allergy Clin Immunol. 2017; 139: 1040-1043Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar6NEMO E315A18 y 10 moMUD7/8CBBU/CY/ATGCSA, prednisoneDied +367 Mycobacterium infectionE1Chandrakasan S. Marsh R.A. Uzel G. Holland S.M. Shah K.N. Bleesing J. Outcome of patients with NEMO deficiency following allogeneic hematopoietic cell transplant.J Allergy Clin Immunol. 2017; 139: 1040-1043Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar7NEMOc.1167_1168 insC3 yMUD2/6CBFlu/Mel/ATGMTX, tacrolimusGrade ISkin GvHDAlive1E2Tono C. Takahashi Y. Terui K. Sasaki S. Kamio T. 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Rizzi M. et al.Deficiency of innate and acquired immunity caused by an IKBKB mutation.N Engl J Med. 2013; 369: 2504-2514Crossref PubMed Scopus (134) Google Scholar27IKBKBc.1292dupG8 moMUDCBMACNAMixed chimerismAlive0.3E20Pannicke U. Baumann B. Fuchs S. Henneke P. Rensing-Ehl A. Rizzi M. et al.Deficiency of innate and acquired immunity caused by an IKBKB mutation.N Engl J Med. 2013; 369: 2504-2514Crossref PubMed Scopus (134) Google ScholarAlem, Alemtuzumab; ATG, antithymocyte globulins; BM, bone marrow; Bu, busulfan; CB, cord blood; CSA, cyclosporine; Cy, cyclophosphamide; Flu, fludarabine; IBD, irritable bowel disease; MAC, myeloablative conditioning; Mel, melphalan; MMF, mycophenolate mofetil; MPD, methylprednisolone; MRD, matched related donor; MTX, methotrexate; MUD, matched unrelated donor; NA, not available; PTLD, posttransplant lymphoproliferative disorder; RIC, reduced intensity conditioning; SMT, smooth muscle tumor; Tre, treosulfan; VOD, veno-occlusive disease. Open table in a new tab Alem, Alemtuzumab; ATG, antithymocyte globulins; BM, bone marrow; Bu, busulfan; CB, cord blood; CSA, cyclosporine; Cy, cyclophosphamide; Flu, fludarabine; IBD, irritable bowel disease; MAC, myeloablative conditioning; Mel, melphalan; MMF, mycophenolate mofetil; MPD, methylprednisolone; MRD, matched related donor; MTX, methotrexate; MUD, matched unrelated donor; NA, not available; PTLD, posttransplant lymphoproliferative disorder; RIC, reduced intensity conditioning; SMT, smooth muscle tumor; Tre, treosulfan; VOD, veno-occlusive disease.