Despite decades of advances in transplant immunology, tissue damage caused by acute allograft rejection remains the primary cause of morbidity and mortality in the transplant recipient. Moreover, the long-term sequelae of lifelong immunosuppression leaves patients at risk for developing a host of other deleterious conditions. Controlled drug delivery using micro- and nanoparticles (MNPs) is an effective way to deliver higher local doses of a given drug to specific tissues and cells while mitigating systemic effects. Herein, we review several descriptions of MNP immunotherapies aimed at prolonging allograft survival. We also discuss developments in the field of biomimetic drug delivery that use MNP constructs to induce and recruit our bodies' own suppressive immune cells. Finally, we comment on the regulatory pathway associated with these drug delivery systems. Collectively, it is our hope the studies described in this review will help to usher in a new era of immunotherapy in organ transplantation.
For individuals who sustain devastating composite tissue loss, vascularized composite allotransplantation (VCA; e.g., hand and face transplantation) has the potential to restore appearance and function of the damaged tissues. As with solid organ transplantation, however, rejection must be controlled by multidrug systemic immunosuppression with substantial side effects. As an alternative therapeutic approach inspired by natural mechanisms the body uses to control inflammation, we developed a system to enrich regulatory T cells (Tregs) in an allograft. Microparticles were engineered to sustainably release TGF-β1, IL-2, and rapamycin, to induce Treg differentiation from naïve T cells. In a rat hindlimb VCA model, local administration of this Treg-inducing system, referred to as TRI-MP, prolonged allograft survival indefinitely without long-term systemic immunosuppression. TRI-MP treatment reduced expression of inflammatory mediators and enhanced expression of Treg-associated cytokines in allograft tissue. TRI-MP also enriched Treg and reduced inflammatory Th1 populations in allograft draining lymph nodes. This local immunotherapy imparted systemic donor-specific tolerance in otherwise immunocompetent rats, as evidenced by acceptance of secondary skin grafts from the hindlimb donor strain and rejection of skin grafts from a third-party donor strain. Ultimately, this therapeutic approach may reduce, or even eliminate, the need for systemic immunosuppression in VCA or solid organ transplantation.
X-ray crystallographic studies, low-temperature X H and 13C NMR studies, and 27Al NMR studies of a series of homoleptic tricyclopentadienylalum inum compounds [(CßHs^Al (1 ), (MeCßHJsAl (2 ), ( l,2 ,4 -Me3C5H2)3Al (3), ( l , 2 ,3 ,4*Me4C5H )3Al (4)] are reported along w ith ab initio calculations on model cyclopentadienylaluminum compounds. The ring-coordination geometries exhibited by the tricyclopentadienylaluminum compounds in the solid state vary with the number of methyl substituents on the cyclopentadienyl rings. The X-ray crystal structure of compound 1 revealed two unique m olecules in the unit cell, one w ith an {rf, rji'5, rf3} combination of ring geometries and the other w ith an {t/2, j/1* 6, rj1} combination of ring-coordination geometries. In the crystal structure of compound 3, one cyclopentadienyl ring is coordinated rf to the aluminum while the other two rings are if. Compound 4 exhibits monohapto coordination of all three tetram ethyl-substituted cyclopentadienyl rings in the solid state. These compounds are highly fluxional in solution and exhibit averaged 1H and 13C NMR spectra in the fast-exchange limit at temperatures as low as -1 1 0 °C. This behavior is explained by the ab initio calculations on model cyclopentadienylalum inum compounds which reveal almost negligible (1 -2 kcal/mol) energy differences betw een different ring hapticities (i;1, rf, rf, rf). Introduction «The cyclopentadienyl ligand is probably best known for its pentahapto-coordination geometiy with transition metals. In the absence of accessible d orbitals, jr-type interactions are weaker, and deviation from 775-geometry by "ring slippage" is often observed. These "ringslipped" (rj1, rf¡ if) structures are more commonly observed among the cyclopentadienyl-main-groupmetal compounds.1" 3 Along with these ring-slipped geometries, cyclopentadienyl compounds of the maingroup elements exhibit varying degrees of fluxionality. Two different sigmatropic processes have been identified experimentally for a-bonded (rj1) species, a 1 ,2-hydrogen shift and a 1,2-shift of the main-group element.4 De tailed mechanistic information on these systems has been obtained, where possible, with the help of variable temper ature NMR techniques.In the case of aluminum, rearrangements are too fast at accessible temperatures to be monitored by NMR. Moreover, equilibrium structures are frequently not rf but ?;L5, rf, or rf> which complicates the discussion of "the sigmatropic process". Nevertheless, it has gener ally been assumed, by extrapolation from experimen tally characterizable systems, that a similar "ringwhizzing"5-8 mechanism is responsible for the dynamic behavior observed in the X H and 13C NMR spectra of cyclopentadienylaluminum compounds. Gas-phase elee-
Vascularized composite allotransplantation (VCA) encompasses face and limb transplantation, but as with organ transplantation, it requires lifelong regimens of immunosuppressive drugs to prevent rejection. To achieve donor-specific immune tolerance and reduce the need for systemic immunosuppression, we developed a synthetic drug delivery system that mimics a strategy our bodies naturally use to recruit regulatory T cells (T reg ) to suppress inflammation. Specifically, a microparticle-based system engineered to release the T reg -recruiting chemokine CCL22 was used in a rodent hindlimb VCA model. These "Recruitment-MP" prolonged hindlimb allograft survival indefinitely (>200 days) and promoted donor-specific tolerance. Recruitment-MP treatment enriched T reg populations in allograft skin and draining lymph nodes and enhanced T reg function without affecting the proliferative capacity of conventional T cells. With implications for clinical translation, synthetic human CCL22 induced preferential migration of human T reg in vitro. Collectively, these results suggest that Recruitment-MP promote donor-specific immune tolerance via local enrichment of suppressive T reg .
A 51-year-old male took advantage of a readjustment of his lower-leg prosthesis to have it revarnished on the exterior and the upper part of the interior. Use of the newly-varnished prosthesis coincided with the appearance of pruriginous papulo-erythematous lesions in the area of the amputation stump and thigh with, in some places, hyperkeratotic lesions. Itchy lesions spread to the hands, upper limbs, left lower limb and trunk, sparing the face and scalp. After ceasing use of the prosthesis, the patient improved greatly.He was patch tested with the GEIDC standard series, our prosthesis series, a plastics and glues series (Chemotechnique), and a meth(arylate) series (Chemotechnique), with positive ( + +) reactions at 48 and 96 h to: methyl methacrylate (2%), ethyl methacrylate (2%), hydroxyethyl methacrylate (2%), hydroxypropyl methacrylate (2%), methacrylic acid (0.1 %), acrylonitrile (0.1 %), butyl methacrylate (2% ), butyl acrylate (0.1% ), ethylhexyl acrylate (0.1% ), hydroxypropyl acrylate (0.1% ), ethyleneglycol dimethacrylate (2%), triethyleneglycol dimethacrylate (2%), butanediol dimethacrylate (2%), urethane dime_thacrylate (2% ), and triethyleneglycol diacrylate (0.1 %), all pet.In general, prostheses cause few problems other than traumatic (friction). This sensitization was caused by high-resistance varnishes, which are usually of 2 types: (i) polyurethane resins (isocyanates), associated with acrylic and methacrylic resins; (ii) polyurethane resins associated with polyester resins.At present, formaldehyde and phenol-formaldehyde resins, and above all, paratertiarybutylphenolformaldehyde resin, are scarcely used.Chemists comment that sensitization is produced because resins in the varnishes are not completely cured.Prevention of cases of contact dermatitis consists in adequate treatment and lining the interior of the prosthesis with Teflon and/or silicone.Recently, Foussereau et al.(1) described the first case of dermatitis, caused by an amputation prosthesis (above-knee), to be attributed to methacrylic resins, with positive patch tests to methyl methacrylate and triethyleneglycol dimethacrylate (both 2% pet.).
Properties and applications of technologically important inorganic compounds of titanium are surveyed. The most important compound is titanium dioxide which, because of its high refractive index, is manufactured as a white pigment at a scale of ca \documentclass{article}\usepackage{amssymb}\pagestyle{empty}\begin{document}${4\times 10^{6}{\hskip0.167em}{\hskip0.167em}{\rm{t}}/{\rm{yr}}}$\end{document} . Raw materials and pigment production processes are reviewed. Mixed oxides, eg, barium titanate, are important raw materials for electroceramics. Titanium hydrides provide a convenient method of hydrogen storage. Titanium boride, titanium carbide, and titanium nitride are used as components of hard materials, eg, for cutting tools. They are electrically conducting. The chlorides are the most important halides. Titanium trichloride is the basis of widely used polymerization catalysts. Titanium tetrachloride is an intermediate in the production of both titanium metal and (via the chloride process) titanium dioxide pigment. Titanium dioxide pigment is also made (in the sulfate process) by precipitation from solutions of titanium in sulfuric acid. Titanium sulfides may be used as cathodes in high efficiency batteries. The properties of some titanium compounds with silicon and phosphorus are reviewed. Analytical methods and health and safety aspects are summarized.
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