Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand

Abstract

X-linked hyper IgM syndrome (XHM) is a combined immune deficiency disorder caused by genetic alterations in CD40ligand. The purpose of this study was to investigate the safety and efficacy of recombinant CD40 ligand (rCD40L) in the treatment of the disease. Three children were administered rCD40L subcutaneously 3 times per week at 0.03 mg/kg for 22 weeks, and after a 12-week drug-free interval, the dose was increased to 0.05 mg/kg for an additional 22 weeks of treatment. Although specific antibody responses to T cell-dependent antigens was lacking, administration of rCD40 resulted in acquisition of the capacity to mount cutaneous delayed type hypersensitivity reactions that disappeared during the drug-free interval as well as the postbiologic follow-up period. [1][2][3] The cognate interaction between CD40L expressed on activated CD4 ϩ T cells and CD40 expressed constitutively on B cells leads to B-cell proliferation, somatic hypermutation in the immunoglobulin variable region, and immunoglobulin class switch recombination from IgM to IgG, IgA, and IgE. [4][5][6] Humans with mutations in the genes encoding CD40L have skewed IgM antibody responses and a markedly diminished or absent IgG response to protein antigens. 7-9 CD40 engagement on the surface of dendritic cells also influences dendritic cell maturation and activation. 8,10 It thus promotes the expression of factors that promote T-cell priming such as costimulatory molecules B7.1 (CD80) and B7.2 (CD86), IL-12 secretion, and the release of chemokines. 10,11 Indeed, humans and mice with CD40L deficiency exhibit defective T-cell function that manifests by a marked predisposition to develop opportunistic infections with Pneumocystis jerovici, Toxoplasma gondii, and Cryptosporidium species as well as an increased tendency to develop malignancies. [12][13][14][15] The IgG/IgA deficiency and associated humoral immune abnormalities in patients with XHM is effectively controlled by ␥ globulin replacement therapy (intravenous immunoglobulin [IVIG] therapy). 13,16 However, despite such treatment, the majority of patients die in the second decade of life as a consequence of impaired T-cell function. 13,17 Bone marrow transplantation is an effective treatment for patients with XHM, especially if performed early in life before the onset of secondary opportunistic infection, 18,19 although the need for matched related donors and the associated morbidity and mortality of the transplant impact on its clinical application. 20,21 Identification of CD40L as an important signaling molecule led to the development of a soluble form of recombinant CD40 ligand (rCD40L) that could be used in various clinical situations. 22,23 This trimeric form of human rCD40L was generated using an isoleucine zipper that is capable of activating the CD40 receptor (Amgen). We first conducted preclinical studies in a murine model of XHM in which the CD40 ligand was disrupted through genetic engineering revealed that administration of CD40 agonists or recombinant murine CD40L trimer reversed the c...

Successful haploidentical PBSCT with subsequent T‐cell addbacks in a boy with HyperIgM syndrome presenting as severe congenital neutropenia

“…Despite the rhG‐CSF treatment, IVIg substitution, and antimicrobial prophylaxis, a significant proportion of children with XHIGM still die unless they are cured by allogeneic HSCT (2, 4, 9). Recombinant CD40L is capable of improving T‐cell function in patients with XHIGM; however, the effect is only partial and transient (10).…”

Design of CD40 Agonists and Their Use in Growing B Cells for Cancer Immunotherapy

“…The sCD40LT was given s.c. in the left forearm and there was partial restoration of lymph node architecture in the left axilla, but not in the contralateral right axilla which indicates a local and not systemic effect. In addition to the histological changes in lymph nodes, these boys developed the ability to respond to skin test antigens with a delayed-type hypersensitivity response and had restored function of their Th1 CD4+ T cells (42). This suggests that sCD40LT could be a useful and safe adjuvant for vaccines in humans.…”

Transitional cell carcinoma in a patient with X‐linked hyperimmunoglobulin M syndrome

“…Recent studies have also shown that CD40 ligand immunotherapy, delivery by attenuated Salmonella typhimurium or adenovirus, has therapeutic effects on hematologic malignancies and some solid tumors in mice . Furthermore, s.c. recombinant CD40 ligand in three children with XHIGM resulted in positive delayed‐type hypersensitivity reaction, restored T‐helper cell function, and synthesis of effector cytokines during the treatment period . This raises the possibility of future amplification of this ligand in patients with XHIGM, which may reduce both the risk of developing infection, and malignancy.…”