Specific immunotherapy of experimental myasthenia gravis in vitro and in vivo: The Guided Missile strategy

Current immunotherapy of myasthenia gravis (MG) is often effective, but entails risks of infection and neoplasia. The "Guided Missile" strategy described here is designed to target and eliminate the individual's unique AChR-specific T cell repertoire, without otherwise interfering with the immune system. We genetically engineered dendritic cells to present AChR epitopes and simultaneously express Fas ligand in an ongoing EAMG model. In both in vitro and in vivo experiments, these engineered cells specifically killed AChR-responsive T cells without otherwise damaging the immune system. AChR antibodies were markedly reduced in the treated mice. Translation of this method to treat human MG is possible.     

Intensive therapy of DIC-syndrome in patients with acute renal insufficiency caused by long-term crush syndrome

Impairment of parenchymatous organs, primarily kidneys, responsible for their dysfunction in crush syndrome results in many respects from disseminated intravascular coagulation (DIC). It is also associated with hemorrhagic complications. It is demonstrated that treatment modalities aimed at arrest of DIC syndrome (plasmapheresis, heparin, dysaggregation drugs, transfusions of large amounts of fresh frozen plasma) stopped bleeding and septic shock in 12 patients with crush syndrome following the earthquake in Armenia (1988).     

Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints

The treatment of chronic inflammatory diseases is complicated by their unpredictable, relapsing clinical course. Here, we describe a new strategy in which an inflammation-regulated therapeutic transgene is introduced into the joints to prevent recurrence of arthritis. To this end, we designed a recombinant adenoviral vector containing a two-component, inflammation-inducible promoter controlling the expression of human IL-10 (hIL-10) cDNA. When tested in vitro, this system had a low-level basal activity and was activated four to five orders of magnitude by various inflammatory stimuli, including TNF-alpha, IL-1 beta, IL-6, and LPS. When introduced in joints of rats with recurrent streptococcal cell wall-induced arthritis, the IL-10 transgene was induced in parallel with disease recurrence and effectively prevented the influx of inflammatory cells and the associated swelling of the joints. Levels of inflammation-inducible hIL-10 protein within the joints correlated closely with the severity of recurrence. An endogenously regulated therapeutic transgene can thus establish negative feedback and restore homeostasis in vivo while minimizing host exposure to the recombinant drug.     

Functional status of the hemostatic and fibrinolytic systems in patients with clinical variants of chronic glomerulonephritis

Function of hemostasis and fibrinolysis was investigated in 152 patients with chronic glomerulonephritis (CGN). Of these, 63 patients presented with an isolated urinary, 49 with hypertensive and 39 with nephrotic syndromes. The patients' groups showed differences in the intensity of the derangement of hemocoagulation and fibrinolysis. The patients with hypertensive CGN manifested different types of responses on the part of thrombin and plasmin, depending on the initial magnitudes of arterial pressure.     

Use of plasmapheresis in the nephrotic syndrome

Plasmapheresis efficacy was demonstrated in the treatment of the nephrotic syndrome as a manifestation of various types of glomerulonephritis. Plasmapheresis could be used independently for the treatment of the nephrotic syndrome. It was shown to be a method of choice in case of the impossibility of common therapy. Plasmapheresis was well tolerated by patients causing no complications.     

T cell receptor transgenic mice recognizing the immunodominant epitope of the Torpedo californica acetylcholine receptor

Myasthenia gravis (MG) is an autoimmune disease caused by T cell-dependent antibody-mediated reduction of acetylcholine receptors (AChR) at the neuromuscular junction. Immunization of animals with Torpedo californica AChR (TAChR) results in an experimental model of MG. We used the variable regions of alpha and beta T cell receptor (TCR) genes recognizing an immunodominant peptide containing amino acids 146-162 from the alpha subunit of TAChR presented in the context of I-A(b) to generate TCR-transgenic mice. We found that the transgenic TCR was strongly positively selected and that transgenic T cells proliferated robustly to the immunodominant peptide and TAChR. Unexpectedly, there was a variable paucity of B cells in the blood and spleen from transgenic mice, which averaged about 16% of peripheral blood lymphocytes, compared to 55% in wild-type B6 mice. Unselected transgenic mice immunized with TAChR exhibited weak anti-TAChR antibody responses. However, transgenic mice selected to have relatively higher B cell numbers produced anti-TAChR titers equal to B6 mice and a predominance of Th1-induced antibody isotypes were observed in certain experiments. The incidence and severity of clinical disease was variable following immunizations. These mice should be useful for studying the pathogenesis and treatment of MG.     

The blood coagulation potential in experimental nephrotoxic glomerulonephritis

An experimental model of nephrotoxic glomerulonephritis was used to study the functional state of the hemostasis and fibrinolysis systems during the course of the disease in 59 rabbits. The hemocoagulation processes occurred in phases in different periods of nephrotoxic nephritis. The authors attempted to link up these changes with the immune shifts occurring in the animal's organism after administration of nephrotoxic serum.     

Correction of blood rheological disorders in patients with chronic kidney failure using heparin and antiaggregants

The state of microcirculation and blood rheology was studied in 32 patients with chronic renal insufficiency. Improved microcirculation and the reduction of clinico-laboratory indices of the DIC-syndrome were noted against a background of heparin and antiaggregant therapy in patients on programmed hemodialysis as well as in patients receiving systemic conservative therapy. In both groups of patients blood pressure decreased in parallel with a decrease in the level of creatinine and urea; a tendency toward improved renal function was noted.