Tolerance to MHC class II disparate allografts through genetic modification of bone marrow

Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-Ab (I-Ab) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction

Transparent ferroelectric crystals with ultrahigh piezoelectricity

Transparent piezoelectrics are highly desirable for numerous hybrid ultrasound-optical devices ranging from photoacoustic imaging transducers to transparent actuators for haptic applications1-7. However, it is challenging to achieve high piezoelectricity and perfect transparency simultaneously because most high-performance piezoelectrics are ferroelectrics that contain high-density light-scattering domain walls. Here, through a combination of phase-field simulations and experiments, we demonstrate a relatively simple method of using an alternating-current electric field to engineer the domain structures of originally opaque rhombohedral Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) crystals to simultaneously generate near-perfect transparency, an ultrahigh piezoelectric coefficient d33 (greater than 2,100 picocoulombs per newton), an excellent electromechanical coupling factor k33 (about 94 per cent) and a large electro-optical coefficient γ33 (approximately 220 picometres per volt), which is far beyond the performance of the commonly used transparent ferroelectric crystal LiNbO3. We find that increasing the domain size leads to a higher d33 value for the [001]-oriented rhombohedral PMN-PT crystals, challenging the conventional wisdom that decreasing the domain size always results in higher piezoelectricity8-10. This work presents a paradigm for achieving high transparency and piezoelectricity by ferroelectric domain engineering, and we expect the transparent ferroelectric crystals reported here to provide a route to a wide range of hybrid device applications, such as medical imaging, self-energy-harvesting touch screens and invisible robotic devices

Prevention of type 1 diabetes by gene therapy

The autoimmune disease type 1 diabetes in humans and NOD mice is determined by multiple genetic factors, among the strongest of which is the inheritance of diabetes-permissive MHC class II alleles associated with susceptibility to disease. Here we examined whether expression of MHC class II alleles associated with resistance to disease could be used to prevent the occurrence of diabetes. Expression of diabetes-resistant MHC class II I-Aβ chain molecules in NOD mice following retroviral transduction of autologous bone marrow hematopoietic stem cells prevented the development of autoreactive T cells by intrathymic deletion and protected the mice from the development of insulitis and diabetes. These data suggest that type 1 diabetes could be prevented in individuals expressing MHC alleles associated with susceptibility to disease by restoration of protective MHC class II expression through genetic engineering of hematopoietic stem cells