Nowadays, the most wildly used regimens for graft-versus-host disease (GvHD) prophylaxis in haplo-hematopoietic stem cell transplantation (Haplo-HSCT) are based on in vivo T-cell depletion (TCD) with anti-thymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCy). To improve the efficiency of GvHD prophylaxis in haploidentical peripheral blood stem cell transplantation combined with unrelated cord blood (Haplo-PBSCT-Cord), a novel regimen, which is composed of low dose of ATG (5 mg/kg) and low-dose PTCy (50 mg/kg) for GvHD prophylaxis, was evaluated in a prospective phase II clinical trial (Clinicaltrials.org NCT03395860). Thirty-two patients diagnosed with hematological malignancies were enrolled in this trial. All patients received myeloablative conditioning regimens except for three patients. The cumulative incidences (CIs) of grades II-IV and III-IV acute GvHD were 19.4% (95% CI, 5.5−33.3%) and 6.9% (95% CI, 0−16.3%) by day 100, respectively. The 1-year probability of relapse, disease free survival (DFS) and overall survival (OS) was 25.1% (95% CI, 7.3−42.9%), 59% (95% CI, 33.3−84.7%) and 78.4% (95% CI, 63−93.8%), respectively. The CIs of CMV and EBV reactivation by day 180 were 37.5% (95% CI, 19.8−55.2%) and 40.6% (95% CI, 22.6−58.6%), respectively. The results suggested that low-dose ATG with low-dose PTCy as GvHD prophylaxis in Haplo-PBSCT-Cord had promising activity.

In the present work, we report a quantitative understanding on how to generate hydroxyl radicals from NO(2) and H(2)O in the troposphere upon photoexcitation at 410 nm by using multiconfigurational perturbation theory and density functional theory. The conical intersections dominate the nonadiabatic relaxation processes after NO(2) irradiated at approximately 410 nm in the troposphere and further control the generation of OH radical by means of hydrogen abstraction. In agreement with two-component fluorescence observed by laser techniques, there are two different photophysical relaxation channels along decreasing and increasing O-N-O angle of NO(2). In the former case, the conical intersection between B(2)B(1) and A(2)B(2) (CI ((2)B(2)/(2)B(1)) first funnels NO(2) out of the Franck-Condon region of B(2)B(1) and relaxes to the A(2)B(2) surface. Following the primary relaxation, the conical intersection between A(2)B(2) and X(2)A(1) (CI((2)B(2)/(2)A(1))) drives NO(2) to decay into highly vibrationally excited X(2)A(1) state that is more than 20,000 cm(-1) above zeroth-order |n(1),n(2),n(3) = 0 vibrational level. In the latter case, increasing the O-N-O angle leads NO(2) to relax to a minimum of B(2)B(1) with a linear O-N-O arrangement. This minimum point is also funnel region between B(2)B(1) and X(2)A(1) (CI((2)B(1)/(2)A(1))) and leads NO(2) to relax into a highly vibrationally excited X(2)A(1) state. The high energetic level of vibrationally excited state has enough energy to overcome the barrier of hydrogen abstraction (40-50 kcal/mol) from water vapor, producing OH ((2)Pi(3/2)) radicals. The collision between NO(2) and H(2)O molecules not only is a precondition of hydrogen abstraction but induces the faster internal conversion (CIIC) via conical intersections. The faster internal conversion favors more energy transfer from electronically excited states into highly vibrationally excited X(2)A(1) states. The collision (i.e., the heat motion of molecules) functions as the trigger and accelerator in the generation of OH radicals from NO(2) and H(2)O in the troposphere.

Data from both animal models and humans have demonstrated that effector memory T cells (T EM ) and central memory T cells (T CM ) from unprimed donors have decreased ability to induce graft-vs-host disease (GVHD). Allospecific T EM from primed donors do not mediate GVHD. However, the potential of alloreactive T CM to induce GVHD is not clear. In this study, we sought to answer this question using a novel GVHD model induced by T cell receptor (TCR) transgenic OT-II T cells. Separated from OT-II mice immunized with OVA protein 8 weeks earlier, the allospecific CD44 high T CM were able to mediate skin graft rejection after transfer to naive mice, yet had dramatically decreased ability to induce GVHD. We also found that these allospecific CD44 high T CM persisted in GVHD target organs for more than 30 days post-transplantation, while the expansion of these cells was dramatically decreased during GVHD, suggesting an anergic or exhausted state. These observations provide insights into how allospecific CD4 + T CM respond to alloantigen during GVHD and underscore the fundamental difference of alloresponses mediated by allospecific T CM in graft rejection and GVHD settings.