Clinical review: Vasculitis on the intensive care unit – part 2: treatment and prognosis

The second part of this review addresses the treatment and prognosis of the vasculitides Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and polyarteritis nodosa. Treatment regimens consist of an initial remission phase with aggressive immunosuppression, followed by a more prolonged maintenance phase using less toxic agents and doses. This review focuses on the initial treatment of fulminant vasculitis, the mainstay of which remains immunosuppression with steroids and cyclophosphamide. For Wegener's granulomatosis and microscopic polyangiitis plasma exchange can be considered for first-line therapy in patients with acute renal failure and/or pulmonary haemorrhage. Refractory disease is rare and is usually due to inadequate treatment. The vasculitides provide a particular challenge for the critical care team. Particular aspects of major organ support related to these conditions are discussed. Effective treatment has revolutionized the prognosis of these conditions. However, mortality is still approximately 50% for those requiring admission to intensive care unit. Furthermore, there is a high morbidity associated with both the diseases themselves and the treatment.     

Delaying rejection in discordant heart xenografts in the rat: efficacy of cyclosporin, prostaglandin I2 and exchange transfusion

If effective modes of prevention of hyperacute rejection were available, the problem of the absence of enough suitable donors could be solved by the use of organ xenografts. Organ xenograft rejection is principally mediated by preformed antibodies which are responsible for the hyperacute pattern of rejection. We decided therefore to study various methods of prevention of rejection in the guinea pig to Lewis rat combination (donor-recipient discordant species) in which hyperacute rejection is particularly intense. Three series of experiments were performed. In the first series immunosuppression of the recipient was induced using an oral solution of cyclosporin A. In the second series antiplatelet-aggregation therapy was administered to the recipient, using intravenous prostacyclin (PGI2). In the third series antibody depletion of the recipient was attempted using exchange transfusion with or without prostacyclin perfusion. The most significant (p less than 0.01) prolongation of graft survival time was observed when combining exchange transfusion (8 ml) and PGI2 infusion (620 ng/kg/min). This observation suggests that, if antibody depletion in the recipient is the primary goal, measures aiming at reducing the consequences of the antigen-antibody reaction are also necessary to improve the results of organ xenografting.     

Co-expression of B7-1 and ICAM-1 on tumors is required for rejection and the establishment of a memory response

Although the transfection of B7-1 cDNA into a few mouse tumor cell lines can induce anti-tumor T cell immunity, its expression alone is ineffective in many other tumor cell lines tested. We were interested to study what factors limit B7-1 co-stimulatory activity, and decided to investigate whether B7-1 requires the cooperation of ICAM-1 to provide the minimal co-stimulatory signal for establishing an efficient anti-tumor immunity. We show that the transfection of B7-1 cDNA into three ICAM-1⁺ (plasmocytoma J558L, T lymphomas EL-4 and RMA), but not into two ICAM-1^? tumor cell lines (adenocarcinoma TS/A and melanoma B16.F1), is sufficient to induce their complete rejection in syngeneic mice. The expression of ICAM-1 is necessary for the rejection of the B7 expressing tumors, since the primary response elicited by B7-1⁺ EL-4 and RMA clones expressing reduced levels of ICAM-1 is severely reduced. Furthermore, super-transfection of ICAM-1 cDNA into B7-1⁺ adenocarcinoma and melanoma clones optimizes their primary rejection. Histologic examination of transfected tumors reveals that B7-1 and ICAM-1 exert a potent pro-inflammatory activity. The intra-tumor infiltration is composed of both eosinophils and lymphomono-cytes, and is already massive 5 days after the tumor challenge. The primary rejection of the B7-1⁺ ICAM-1⁺ tumors depends critically on CD8⁺ T cells, natural killer cells and granulocytes, but is independent of CD4⁺ T cells. Remarkably, in addition to its effects on the early phases of the immune response, the co-expression of ICAM-1 and B7-1 on tumors is also necessary for the efficient induction of a memory response. In fact, only the primary challenge with B7-1⁺, ICAM-1⁺ tumor cells protects the majority of the mice from a second injection of parental tumor cells. Collectively, our findings indicate that B7-1 and ICAM-1 are fundamental components for triggering the primary rejection of tumors and establishing a protective memory response. These findings may help to define new strategies for the rational application of co-stimulation in tumor immunotherapy.     

Serum pepsinogen I and gastrin concentrations in children positive for Helicobacter pylori.

Serum pepsinogen I, serum gastrin concentration, and inflammatory scores were measured in a population of 71 children undergoing upper gastrointestinal endoscopy for investigation of upper abdominal pain. Forty four were initially colonised with Helicobacter pylori. The indices were measured before treatment (in 71 children), one month (in 41 children), and six months (in 21 children) after stopping treatment. Before treatment there was a significant correlation between serum pepsinogen concentration, total inflammatory score, and H pylori state, but no correlation between serum gastrin concentrations and H pylori state. Similarly, the total inflammatory score and serum pepsinogen concentrations were significantly correlated. There was no such correlation in children negative for H pylori. After treatment the inflammatory score improved in those patients in whom H pylori had been eradicated. There was also a significant fall in serum pepsinogen I and serum gastrin concentration in those patients in whom H pylori had been eradicated. These results were similar to those found six months after treatment had been stopped. These findings suggest that the serum pepsinogen I concentration could be considered a useful marker for gastritis and can be used as an index of severity of gastritis in H pylori positive subjects. The measurement of serum gastrin concentrations does not give useful information.     

A monoclonal antibody against a new differentiation antigen of thymocytes

B14-2-14 is a monoclonal cytotoxic IgM antibody which reacts with thymocytes of all mouse strains tested. The fraction of positive cells (by visual immunofluorescence) varies between strains from about 25-45% in A.CA to 65-85% in C57BL/6, and high levels are dominant in F1 hybrids. In the periphery, the antigen is found on a few percent of lymph node and not on splenic T cells, and it is absent in nude mice. Among thymocytes, the distribution of the B14 determinant largely overlaps with that of the TL antigen and of molecules binding peanut agglutinin. The B14 antibody reacts only minimally with hydrocortisone-resistant thymus cells. Biochemical analysis shows that B14 antibody, anti-TL antibody and peanut agglutinin bind to separate molecules. The target of the B14 antibody may be either an immature, thymic form of Thy-1, or another molecule associated with it. Two polypeptides, of 40 and 35 kDa are precipitated by both B14 and anti-Thy-1 antibodies from biosynthetically labeled thymus cell lysates, and two others, of 27 and 17 kDa, from surface-iodinated thymus cell preparations. B14-2-14 offers an additional method for identification and selection of thymocytes at different stages of differentiation, and should also be useful for studies of the Thy-1 antigen.     

A tumour-associated membrane antigen transiently expressed by normal cells during mitosis

Rabbit antisera raised against antigens solubilized from the membranes of a transplantable Balb/c adenocarcinoma precipitated an antigen that was not expressed by the normal resting mammary gland or any other normal mouse tissue. The same antisera were used to show the presence of this antigen in other mammary adenocarcinomas, although not in tumours of different histological types. The antigen was, however, transiently expressed by mammary gland cells during the hyperplasia that both precedes and accompanies lactation. A connection is sought between the existence of this antigen and the membrane structural changes that take place during mitosis.     

Genetic and functional characterization of an antiserum to the lipid A-specific triggering receptor on murine B lymphocytes.

The inheritance of responsiveness to lipopolysaccharide (LPS), and of a marker recognized in LPS-reactive cells by a heterologous antiserum, was studied in crosses between C3H/HeJ (nonresponder) and C3H/Tif (high responder) mice. F1 hybrid mice show codominant expression of these traits: (a) LPS-reactive cells are only hlaf as frequent in the hybrids as in the high responder parent; (b) the serologically defined marker is expressed in half as many cells in the hybrids as in the high responder parent. In backcross generations, both LPS responsiveness and this serological marker segregated into high, intermediate, and nonresponders. LPS or free lipid A, but not two other B cell mitogens (lipoprotein, and purified protein derivative of tuberculin), compete with the antiserum for binding to the B cell surface membrane, and are capable of completely inhibiting such binding without interfering with the binding of a-ti-Ig antibodies or complexes to Fc receptors. The addition of an IgG fraction of the antiserum to B cell cultures results in exponetial growth of the cells and in maturation to antibody secretion. This mitogenic activity is dose-depedent and absorbable on spleen cells from LPS high responder mice. Taken together, these observations suggest that this antiserum contains antibodies to the lipid A-specific triggering receptor on B lymphocytes.     

Idiotypic characterization of antibody-induced antibody responses

Anti-idiotypic antisera were produced in syngeneic (C57BL/6) mice against a monoclonal anti-Dextran B512 (Dex) antibody (38-13). In radioimmunoassays, anti-idiotypic antibodies were shown to react with the homologous idiotype, while failing to recognize another monoclonal anti-Dex antibody, independently derived from C57BL/6 mice (D-16). Plaque inhibition tests confirmed the specificity of the anti-idiotypic antibodies and revealed that the 38-13 idiotype is expressed by about half of all anti-Dex antibodies produced in C57BL/6, but not in CBA mice. Injection of normal (but not athymic) C57BL/6 mice with low doses of 38-13 monoclonal antibodies, contained culture supernatants or ascitic fluids, resulted in a 10-20 fold increase in the numbers of anti-Dex PFC detected in the spleen 5 days later, the majority of which carried the 38-13 idiotype.