Anti-CLTA monoclonal antibody, clone TQN285

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for a variety of hematological diseases; however, it is still associated with substantial morbidity and mortality. Transplant-related mortality (TRM) after HSCT depends mainly on the toxicity of the conditioning regimen, infections, and graft-versus-host disease. The purpose of this study was to identify the association between CTLA-4 single nucleotide polymorphisms and TRM in children undergoing allogeneic HSCT. 153 donors and 153 children with acute lymphoblastic leukemia, acute myeloid leukemia or juvenile myelomonocytic leukemia who had undergone allogeneic HSCT were genotyped of CTLA-4 gene for rs3087243 (CT60G > A), rs231775 (+ 49 A > G) and rs4553808 using TaqMan real-time polymerase chain reaction. We observed a significant association between the donor's CLTA-4 genotype of rs3087243 and TRM in children undergoing allogeneic HSCT. Genotype AG was found in 78 donors (51%), GG in 44 donors (29%) and 31 donors (20%) were homozygous for AA. 30 patients died as a result of transplant-related causes. Interestingly, we observed a significantly reduced TRM in children who were transplanted from a donor with the CTLA-4 genotype GG in comparison to genotype AG or AA (9 versus 19 versus 36%, P = 0.013). In addition, we found significant differences of event-free survival (EFS) depending on the donor's genotype. The EFS was 64, 46 or 32% if the patient was transplanted from a donor with CTLA-4 genotype GG, AG or AA, respectively (P = 0.043). In multivariate analysis, CTLA-4 genotype of rs3087243 was an independent risk factor for TRM (P = 0.011) and EFS (P = 0.035). This study provides first evidence that the CTLA-4 polymorphisms are significant risk factors for TRM and survival in children undergoing allogeneic HSCT and should be evaluated in further trials.

Allergic diseases such as asthma, rhinitis and eczema are increasing in prevalence worldwide, in industrialised countries affecting up to 20% of the population. Regulatory T-cells (Tregs) have been shown to be critical in T-cell homeostasis and in the maintenance of immune responses, such as prevention of autoimmunity and hampering allergic diseases. The so-called 'natural' CD4(+)CD25(+) Tregs and/or IL-10-producing Tr1 cells have been shown to be responsible for the protection of immune tolerance and intact immune reactions following exposure to allergens such as aeroallergens or food allergens. In this regard, both cell-cell contact (through membrane bound TGF-beta or via suppressive molecules such as CLTA-4) and soluble cytokine(TGF-beta and IL-10) dependent mechanisms have been shown to contribute to the ability of Tregs to operate effectively. The transcription factor Foxp3, a member of the forkhead-winged helix family, appears to be critical in the suppressive abilities of regulatory T-cells. Adoptive transfer of CD4(+)CD25(+) Tregs from healthy to diseased animals corroborated and provided further evidence of the vital role of these populations in the prevention or cure of certain autoimmune conditions. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma has also been associated with the induction of IL-10 and TGF-beta producing Tr1 cells as well as Foxp3 expressing CD4(+)CD25(+) T-cells, resulting in the suppression of Th2 cytokine milieu. Activation and expansion of antigen-specific CD4(+)CD25(+) Tregs in vivo using adjuvants such as IL-10 or pharmacological agents such as low dose steroids or vitamin D3 could represent novel approaches to induce antigen-specific tolerance in immune-mediated conditions such as allergic asthma, autoimmune disease and the rejection of transplanted organs in man.