RESUMO
Fludarabine busulfan anti-thymocyte globulin is a common conditioning chemotherapy with reduced toxicity used for transplantation in sickle cell disease (SCD). The dose of busulfan used in this protocol is variable across studies and centers. The minimum dose that maintains long-term donor chimerism is not well established. We hypothesized that a lower, less-toxic dose could be used to maintain adequate long-lasting chimeras, which might allow for the inclusion of older or comorbid patients with this disease. In our retrospective study of 11 patients, 8-9.6 mg/kg was adequate to maintain chimerism in six patients. A 6 mg/kg dose resulted in transplant rejection in two patients. This suggests that 0.8 mg/kg IV busulfan every 6 h for 8-12 doses (total 8-9.6 mg/kg) is the minimum adequate busulfan dose required to maintain long-lasting chimeras, facilitating the successful withdrawal of immunosuppression in SCD patients who receive this protocol.
Assuntos
Doença Enxerto-Hospedeiro , Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/imunologia , Leucemia/terapia , Antígenos de Neoplasias/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Doadores de Tecidos , TransplantadosRESUMO
Donor T-cell mediated graft versus host (GVH) effects may result from the aggregate alloreactivity to minor histocompatibility antigens (mHA) presented by the human leukocyte antigen (HLA) molecules in each donor-recipient pair undergoing stem-cell transplantation (SCT). Whole exome sequencing has previously demonstrated a large number of non-synonymous single nucleotide polymorphisms (SNP) present in HLA-matched recipients of SCT donors (GVH direction). The nucleotide sequence flanking each of these SNPs was obtained and the amino acid sequence determined. All the possible nonameric peptides incorporating the variant amino acid resulting from these SNPs were interrogated in silico for their likelihood to be presented by the HLA class I molecules using the Immune Epitope Database stabilized matrix method (SMM) and NetMHCpan algorithms. The SMM algorithm predicted that a median of 18,396 peptides weakly bound HLA class I molecules in individual SCT recipients, and 2,254 peptides displayed strong binding. A similar library of presented peptides was identified when the data were interrogated using the NetMHCpan algorithm. The bioinformatic algorithm presented here demonstrates that there may be a high level of mHA variation in HLA-matched individuals, constituting a HLA-specific alloreactivity potential.