SummaryBecause type 1 diabetes (T1D) is a chronic, autoimmune, T cell-mediated disease, interventions affecting T cells are expected to modulate the immune cascade and lead to disease remission. We propose that increased CD4 + CD25 +high T cell apoptosis, a trait we discovered in recent-onset T1D subjects, reflects T1D partial remission within the first 6 months after diagnosis. Apoptosis of forkhead box P3 (FoxP3) + CD4 + CD25 +high T cells, in addition to total daily doses of insulin (TDD), blood glucose, HbA1c and age, were measured in 45 subjects with T1D at various times after diagnosis. Sixteen healthy control subjects were also recruited to the study. Higher CD4 + CD25 +high T cell apoptosis levels were detected within the first 6 months of diagnosis (odds ratio = 1·39, P = 0·009), after adjustment for age, TDD and HbA1c. A proportional hazards model confirmed that the decline of apoptosis after diagnosis of T1D was related significantly to survival time (hazards ratio = 1·08, P = 0·014), with TDD and age also contributing to survival. During this time there was an inverse relationship between CD4+ CD25 +high T cell apoptosis with TDD (r = -0·39, P = 0·008). The CD4 + CD25 +high T cell apoptosis levels decline significantly after the first 6 months from diagnosis of T1D and may help in the close monitoring of autoimmunity. In parallel, there is an increase in TDD during this time. We also propose that CD4 + CD25 +high T cell apoptosis assay can be used to gauge the efficacy of the several immune tolerance induction protocols, now under way.

Alternative donor transplantation is increasingly used for high risk lymphoma patients. We analyzed 1593 transplant recipients (2000 to 2010) and compared transplant outcomes in recipients of 8/8 allele human leukocyte antigen (HLA)-A, -B, -C, and DRB1 matched unrelated donors (MUD; n=1176), 7/8 allele HLA-matched unrelated donors (MMUD; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared to MUD (35%; p=0.004), but similar to UCB recipients (37%; p=0.19), although UCB had lower rates of neutrophil and platelet recovery compared to unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, p=0.003) but similar between UCB and MUD (30% vs 33%; p=0.48). In multivariate analysis UCB recipients had lower risks of acute and chronic graft versus host disease compared with adult donor groups (UCB vs MUD: HR=0.68, p=0.05; HR=0.35; p<0.001). Adjusted 3-year overall survival was comparable (43% MUD, 37% MMUD and 41% UCB). Data highlight that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can expand the curative potential of allotransplant to patients who lack suitable HLA-matched sibling or MUD.

Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4 þ CD25 þ high T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4 þ CD25 þ high T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4 þ CD25 þ high T-cell apoptosis, after adjustment for age, gender and phenotypic status (n ¼ 83, F ¼ 4.04 (d.f. ¼ 3), P ¼ 0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4 þ CD25 þ high apoptosis levels compared with low risk HLA DQB1 control subjects (n ¼ 26, P ¼ 0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4 þ CD25 þ high T-cell apoptosis, which implicates CD4 þ CD25 þ high T-cell apoptosis as a new intermediate trait for T1D.

Allogeneic hematopoietic cell transplantation (HCT) offers the potential to cure hematologic malignancies. Absent an HLA matched donor, HLA mismatched unrelated donors may be used although risks of graft-versus-host disease (GvHD) and treatment related mortality (TRM) are higher. Identification and avoidance of amino acid substitutions and position types (AASPT) conferring higher risks of TRM and GvHD would potentially improve the success of transplantation from single HLA mismatched unrelated donors. Using random forest and logistic regression analyses, we identified 19 AASPT associated with greater risks for at least one adverse transplant outcome: grade III-IV acute GvHD, TRM, lower disease free survival or worse overall survival relative to HLA matched unrelated donors and to other AASPT. When tested in an independent validation cohort of 3,530 patients, none of the AASPT from the training set were validated as high-risk, however. Review of the literature shows that failure to validate original observations is the rule and not the exception in immunobiology and emphasizes the importance of independent validation prior to clinical application. Our current data do not support avoiding any specific class I AASPT for unrelated donors. Additional studies should be performed to fully understand the role of AASPT in HCT outcomes.

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