v. Serial transplantation resulting in tolerance

A. Serial transplantation resulting in tolerance to an unrelated cord blood graft. Goebel WS, Nelson RP Jr, Brahmi Z, Gowan DJ, Towell PJ, Robertson KA, Haut PR. Transplantation 2006;81:1596-9.

The treatment of choice for severe combined immunodeficiency (SCID) is replacement immunoglobulin therapy and hematopoietic stem cell (HSC) transplantation. In addition to the usual sources of hematopoietic stem cells for transplantation, another conceivable source of stem cells for a second child with autosomal-recessive SCID is engrafted hematopoietic cells initially derived from UCB "passaged" first through a similarly affected sibling. If the siblings are human leukocyte antigen (HLA)-identical, the first child's "processing" or UCB cells might render the graft less capable of eliciting graft-versus-host disease (GVHD) in the second recipient.

Stiehm et al (N Engl J Med 1996;335:1811) transplanted paternally derived marrow into a girl with SCID; the graft was obtained from an older sister who had experienced disease correction after receiving two infusions of paternal T-cell-depleted haploidentical marrow several years earlier. The younger child's uneventful course after transplantation was concluded to be a indication that the paternal T cells had acquired immunologic tolerance to relevant HLA antigens, permitting immunologic reconstitution without GVHD.

In this article, the authors report the correction of SCID with umbilical cord blood hematopoetic stem cells obtained from an HLA-matched sibling who had previous received a transplant. The authors indicated that this is the first report of serial transplantation of unrelated HSCs in humans.

Unrelated cord blood (UCB) hematopoietic stem cells were serially transplanted into two HLA-identical siblings with T cell, B cell, natural killer cell severe combined immunodeficiency. Brother A received a 4/6-matched, HLA DRbeta1-identical but class I-disparate UCB graft after myeloablative dosages of busulfan, melphalan, and antithymocyte globulin. He experienced complete donor chimerism, severe acute gastrointestinal GVHD, and limited chronic skin GVHD that resolved with treatment. Two years later, brother B received unfractionated marrow from brother A after reduced-intensity conditioning with cyclophosphamide and antithymocyte globulin. Brother B experienced mixed-donor (i.e. original UCB) chimerism and no histologically documented GVHD. Both brothers are clinically well; brother A is in a fully immunologically reconstituted state.

The uneventful course and progressive increase in donor chimerism after the second transplantation indicates that hematopoietic cells derived from the older brother's marrow engrafted without causing GVHD, suggesting that acquired tolerance to disparate unrelated HLA antigens was achieved.