SUMMARY CD4 T cell activation leads to rapid proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While Teff and Treg prefer distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are poorly understood. Despite expression of multiple glucose transporters, Glut1-deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1-deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased cell survival and Teff differentiation. Importantly, Glut1-deficiency decreased Teff expansion and ability to induce inflammatory disease in vivo. Treg, in contrast, were enriched in vivo and appeared functionally unaffected by Glut1-deficiency and able to suppress Teff irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival.

CALGB 9511 used pegaspargase (PEG-ASP) in lieu of the native enzyme. The aim was to compare differences in overall survival (OS) and disease-free survival (DFS) between patients who did and did not achieve asparagine depletion, defined by enzyme levels greater than 0.03 U/mL plasma for 14 consecutive days after at least 1 of 4 planned PEG-ASP administrations. Samples were available from 85 eligible patients. On univariate analyses, the 22 patients who did not achieve asparagine depletion had inferior OS (P ‫؍‬ .002; hazard ratio [HR] ‫؍‬ 2.37; 95% CI ‫؍‬ 1.38-4.09) and DFS (P ‫؍‬ .012; HR ‫؍‬ 2.21; 95% CI ‫؍‬ 1.19-4.13). After adjusting for age, performance status, leukocyte count, and karyotype in a proportional hazards model, both the OS and DFS HRs decreased to 1.8 (P ‫؍‬ .056; 95% CI ‫؍‬ 1.0-3.2 and P ‫؍‬ .084; 95% CI ‫؍‬ 0.9-3.6, respectively). We conclude that effective asparagine depletion with PEG-ASP is feasible as part of an intensive multiagent therapeutic regimen in adult acute lymphoblastic leukemia and appears as- IntroductionAsparaginase (ASP) hydrolyzes asparagine to aspartate and ammonia. Acute lymphoblastic leukemia (ALL) cells lack asparagine synthetase and are dependent on an exogenous source of asparagine for survival. Rapid depletion of asparagine results in the selective killing of ALL cells, whereas normal cells are able to synthesize asparagine. 1 Three preparations of ASP are available: one from Escherichia coli, one from Erwinia carotovora, and pegaspargase (PEG-ASP), the monoethoxypolyethylene glycol succinimidyl conjugate of E coli L-asparaginase. PEG-ASP has decreased immunogenicity and a longer half-life than the other 2 enzymes 2,3 and maintains asparagine depletion equivalent to higher doses and prolonged administration of the native preparations. 4 The effect of PEG-ASP was previously studied in 3 relapsed 5-7 ALL trials and in 2 pediatric induction 8,9 and 1 adult 10 induction ALL studies. All have shown it to be well tolerated with comparable or better asparagine depletion. A randomized trial 9 in childhood ALL demonstrated a correlation between ASP activity and asparagine depletion. None of those trials demonstrated an effect of asparagine depletion on outcome.The Cancer and Leukemia Group B (CALGB) used PEG-ASP in lieu of the native enzyme during induction and early intensification therapy of adult patients with ALL. The aim of the study was to explore differences in overall survival (OS) and disease-free survival (DFS) of those patients who achieved asparagine depletion compared with those who did not. Patients, materials, and methods PatientsPatients were eligible if they had untreated ALL or acute undifferentiated leukemia. 11 Burkitt-type ALL was excluded. Central immunophenotyping, pathology, and karyotype reviews were required. All patients provided informed consent in accordance with the Declaration of Helsinki. This study received IRB approval from each participating institution. Between July 1995 and December 1997, 104 patients were enrolled; 102 were eligible. PEG...

Several groups, including our own, have independently demonstrated that effector memory T cells from non-alloantigenprimed donors do not cause graft-versushost disease (GVHD). In the current study, we further investigated whether this approach could be extended to all memory T cells, and we studied the underlying mechanisms. Neither total memory T cells nor purified central memory T cells were able to induce GVHD. Memory T cells were at least 3-log less potent than bulk T cells in mediating GVHD. As expected, memory T cells failed to elicit cytotoxicity and proliferated poorly against alloantigens in standard 5-day mixed-lymphocyte cultures. However, the proliferative responses of memory T cells were more comparable with those of bulk and naive T cells when the culture time was shortened. Moreover, the frequencies of IL-2-secreting cells measured by 42-hour enzyme-linked immunosorbent spot (ELISPOT) assay were similar among naive, memory, and bulk T cells. These data indicated that memory T cells are able to respond to alloantigens initially but fail to develop to full potential. The abortive immune response, which was mediated by non-alloantigen-specific memory T cells in response to alloantigens, may explain why memory T cells from unprimed and non-alloantigen-primed donors could not induce GVHD. (Blood. 2007;109:3115-3123)

The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation.