Bone marrow transplantation as treatment for X-linked immunodeficiency with hyper-IgM

Abstract

Summary:We report a 10-year-old boy with a severe form of immunodeficiency with hyper-IgM who underwent successful bone marrow transplantation with his HLAmatched sister as donor. Busulfan (20 mg/kg) and cyclophosphamide (200 mg/kg) were used as conditioning. The post-transplant course was uneventful. He is alive 25 months later with full hematological and immunological reconstitution. Keywords: X-linked immunodeficiency with hyper-IgM; bone marrow transplantation; CD40 ligand X-linked immunodeficiency with hyper-IgM (X-HIM) is characterized by undetectable serum levels of IgG, IgA and IgE and normal or elevated levels of IgM. 1 The underlying defect in these patients is the inability to switch from IgM/IgD secretion to production of the other immunoglobulin isotypes, IgG, IgA and IgE. This rare primary disorder of immunity is caused by mutations affecting the expression of CD40 ligand (CD40 L) on T lymphocytes. 2,3 The gene encoding the CD40 L is located at Xq26 and encompasses 13 kb of genomic DNA. 4 CD40 L is a type II integral transmembrane glycoprotein expressed primarly by activated CD4 ϩ lymphocytes. 3 Interactions between CD40 L ϩ activated CD4 ϩ T cells and B lymphocytes (that constitutionally express CD40) serve as a fundamental membrane signal for B cell growth and differentiation. 5 This interaction normally mediates immunoglobulin class switching by B cells. The consequence of mutations is that CD40 L on T cells cannot interact with the CD40 glycoprotein on the surface of B cells. In addition, interaction between CD40 L activated T cells and antigen presenting cells (which also express CD40) elicits an immune response to intracellular microorganisms. This may explain the susceptibility of a subgroup of patients to severe opportunistic infections particularly those due to Pneumocystis carinii (PC), BCG and cryptosporidium infections. 6 They are also

Hematopoietic Stem Cell Transplantation for CD40 Ligand Deficiency: Single Institution Experience

“…Conservative management consists of immunoglobulin replacement therapy, prophylaxis against PJP, granulocyte‐colony stimulating factor (GCSF) for severely neutropenic patients, rCD40L therapy, and measures to decrease the risk of cryptosporidium infections, such as avoiding swimming in ponds and lakes and drinking boiled water . However, the only curative therapy is allogeneic hematopoietic stem cell transplantation (HSCT), as suggested by limited published data . Also, advances in diagnosis, donor selection, preparative regimens, and supportive care have led to improved outcomes following transplantation for primary immunodeficiencies .…”

Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002

“…8 Hematopoietic stem cell transplantation (HSCT) has the potential to cure this T-cell immunodeficiency. [9][10][11][12][13][14][15][16][17] A particular problem during transplantation is reactivation of cryptosporidial infection resulting in diarrhea and acute cholangiopathy. In a study using molecular techniques to detect asymptomatic carriage of cryptosporidial species in primary immunodeficiency patients, 5 of 12 patients with CD40 ligand deficiency were chronically colonized, of whom only 1 had a known history of infection.…”

CD154-CD40 interactions in the control of murine B cell hematopoiesis

“…We could find only two reports describing B cell reconstitution after BMT of these patients. Duplantier et al [37] found that peripheral B cell numbers took some 20 months to return to normal following fully matched sibling BMT of an 8-month-old boy with XHIM, and Bordigoni et al [39] found that in a 10-year-old boy, B cell levels were normal 10 months after BMT. Looking at a large number of older, non-XHIM patients, Storek et al [41] reported that on average, B cell numbers were normal by 1 year after transplantation.…”