A randomized controlled trial of a shared decision making intervention for diabetes prevention for women with a history of gestational diabetes mellitus: The Gestational diabetes Risk Attenuation for New Diabetes (GRAND study).

BACKGROUND: Gestational diabetes mellitus (GDM) is a risk factor for the development of type 2 diabetes. Metformin and lifestyle change through a Diabetes Prevention Program (DPP) are equally effective in preventing diabetes in patients with a GDM history, so women can choose a strategy based on their preferences. This study aims to test whether shared decision making (SDM) can help women with a history of GDM increase adoption of evidence-based strategies and lose weight to lower their risk of incident diabetes in real-world settings. METHODS: This pragmatic randomized controlled trial (RCT) will test the effectiveness of SDM for diabetes prevention among 310 overweight/obese women with a history of GDM and prediabetes from two large health care systems (n = 155 from UCLA Health and n = 155 from Intermountain Healthcare). The primary outcome is the proportion of participants who lose ≥5% body weight at 12 months. Secondary outcomes include uptake of DPP and/or metformin and other patient-reported outcomes such as patient activation and health-related quality of life. Rates of GDM in a subsequent pregnancy will be an exploratory outcome. A descriptive analysis of costs related to SDM implementation will also be conducted. CONCLUSION: This is the first RCT to examine the effectiveness of SDM on weight loss, lifestyle change and/or metformin use, and other patient-reported outcomes in participants with a GDM history at risk of developing diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03766256. Registered on 6 December 2018.

Homeostatic expansion and repertoire regeneration of donor T cells during graft versus host disease is constrained by the host environment.

Graft versus host disease (GVHD) typically results in impaired T-cell reconstitution characterized by lymphopenia and repertoire skewing. One of the major causes of inadequate T-cell reconstitution is that T-cell survival and expansion in the periphery are impaired. In this report, we have performed adoptive transfer studies to determine whether the quantitative reduction in T-cell numbers is due to an intrinsic T-cell defect or whether the environmental milieu deleteriously affects T-cell expansion. These studies demonstrate that T cells obtained from animals with graft-versus-host disease (GVHD) are capable of significant expansion and renormalization of an inverted CD4/CD8 ratio when they are removed from this environment. Moreover, these cells can generate complex T-cell repertoires early after transplantation and are functionally competent to respond to third-party alloantigens. Our data indicate that T cells from mice undergoing GVHD can respond to homeostatic signals in the periphery and are not intrinsically compromised once they are removed from the GVHD environment. We thereby conclude that the host environment and not an intrinsic T-cell defect is primarily responsible for the lack of effective T-cell expansion and diversification of complex T-cell repertoires that occurs during GVHD.

Selective elimination of alloreactive donor T cells attenuates graft-versus-host disease and enhances T-cell reconstitution.

Impaired T-cell immune reconstitution is a major complication after allogeneic bone marrow transplantation (BMT) and is particularly exacerbated in the setting of graft-versus-host disease (GVHD). Conventional approaches to reduce GVHD, such as T-cell depletion or pharmacologic immunosuppression, typically fail to enhance T-cell immunity and often further exacerbate this problem. An alternative strategy to mitigate GVHD severity is the selective elimination of graft-versus-host-reactive donor T cells by using an incorporated thymidine kinase suicide gene. This approach has been shown to effectively reduce GVHD, although the effect of this strategy on T-cell reconstitution is unresolved. We addressed this question in a murine BMT model (C57BL/6 [H-2(b)] --> AKR/J [H-2(k)]) in which donor and recipient differ at major and minor histocompatibility antigens. Lethally irradiated AKR recipients transplanted with T cell-depleted bone marrow plus thymidine kinase-positive T cells followed by post-BMT ganciclovir (GCV) administration had more prompt and complete normalization of the T-cell repertoire than phosphate-buffered saline-treated GVHD control animals. By 60 days after transplantation, mice administered GCV had T-cell repertoires that were virtually indistinguishable from those of mice that underwent transplantation with T cell-depleted bone marrow alone (no GVHD controls) when assayed by T-cell receptor (TCR) spectratyping. In contrast, phosphate-buffered saline-treated animals had persistent skewing in most Vbeta families. T cells obtained from GCV-treated mice also had significantly higher in vitro proliferative responses after posttransplantation inoculation with ovalbumin than GVHD animals, indicating that CD4(+) T-cell responses against a nominal antigen were better preserved in these chimeras. Finally, GCV-treated mice had augmented immune reconstitution in response to exogenous interleukin-7 administration, as evidenced by increased overall spleen cellularity and absolute numbers of T and B cells. This was in contrast to GVHD control animals, which had a blunted response to interleukin-7 administration. These data indicate that GVHD severity can be significantly reduced by selective elimination of alloreactive donor T cells without compromise of T-cell immunity. Moreover, in light of previous studies demonstrating that this strategy can reduce GVHD without loss of alloengraftment and antileukemia reactivity, further examination of this approach in humans seems warranted.