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Background. Posttransplantation infusion of donor bone marrow cells (BMC) can prolong allograft survival in antilymphocyte antibody- (ALA) treated recipients. This study examined the hypothesis that chimerism of donor BMC origin contributes to allograft unresponsiveness. Methods. Survival of day 0 skin grafts from C3H (H2 k ) donors was prolonged on ALA-treated B6AF1 mice by day +7 infusion of BMC from C3H or C3H-H2 02 (H2K d I d D k ) mice. To test for functional chimerism, depletional anti-H2K d antibody was injected at intervals after C3H-H2 02 BMC infusion. To confirm the persistence of active cells in the recipients, cells harvested from bone marrow of ALA- and C3H BMC-treated primary recipients were transferred to secondary ALA-treated recipients. Other recipients were infused on day +21 with additional donor BMC or light-density BMC that had been cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) to promote the differentiation of dendritic cells (DC). Results. Injection of depletional antibody targeting infused BMC interrupted skin graft survival, whether the injection was made on day +7, 2 hr after BMC injection, or as late as day +28. Prolonged graft survival was transferred to secondary recipients with cells recovered from primary recipient marrow as long as 4 weeks after initial donor BMC treatment. Graft survival prolonged by day +7 BMC was further enhanced by infusion on day +21 of light density cultured BMC, although a second dose of unfractionated BMC was inactive. Repeated injection of cultured BMC at 2-week intervals after day +21 prolonged graft survival even further. Conclusions. These data directly demonstrate that at least short-term donor BMC-derived microchimerism is required for prolonged allograft survival. The data further suggest that the active chimeric cells persist in recipient marrow. Finally, the beneficial effect of late infusion of cultured cells containing partially differentiated DC suggest that DC may be the active chimeric cells.

The term “induction therapy” is used to describe antilymphocyte antibody pharmacologics that are parenterally administered for a short course immediately posttransplant. The origin of the term “induction” is difficult to trace (it may relate to similar practices applied in the field of oncology); other words such as “priming” and “conditioning” have also been used.

The authors analysed CD4+ subset populations and particularly subset killing in order to evaluate the presence of antilymphocyte antibody against CD4+ subsets in patients with IgA nephropathy (IgA N). This study was performed in 45 patients with IgA N, 30 patients with other forms of glomerulonephritis and 30 healthy controls. CD4+, CD4+CD45R- and CD4+CD45R+ cells in the peripheral blood were counted by a flow cytometric analysis, and those cell killings were analysed by microcytotoxic assays. The percentage of circulating CD4+CD45R+ cells was significantly decreased in IgA N, and the percentage of CD4+CD45R+ cell killing was significantly elevated in IgA N compared with other groups. There was a significant negative correlation between the percentage of CD4+CD45R+ cells present in IgA N patients' peripheral blood lymphocytes and the killing CD4+CD45R+ cells by the same patients' serum. Both a depletion of CD4+CD45R+ cells in peripheral blood lymphocytes and an elevation of CD4+CD45R+ cell killing correlated with the grade of mesangial proliferation in patients with IgA N. However, there were no correlations in other clinicopathological indices. These results suggest that low levels of antilymphocyte antibodies against CD4+CD45R+ cells were present in patients with IgA N, who showed a depletion of CD4+CD45R+ cells in the peripheral blood. These antibodies were strongly associated with the elimination of CD4+CD45R+ cells and the proliferation of glomerular mesangial cells in patients with IgA N.

To evaluate the efficacy, safety, and cost of preemptive ganciclovir therapy in cytomegalovirus (CMV)-seropositive renal transplant recipients treated with antilymphocyte antibody (ALA) preparations.A prospective, randomized trial at a 650-bed tertiary medical center hospital.Forty consecutive CMV-seropositive renal allograft recipients who underwent transplantation between January 1992 and January 1994 and were treated with ALA for induction immunosuppression or acute rejection therapy.The incidence and severity of CMV disease, length of hospitalization, and patient and allograft survival.Cytomegalovirus infection prophylaxis by use of intravenous ganciclovir during ALA therapy was administered to 22 patients (group 1) and the results were compared with those obtained in 18 control patients who did not receive prophylaxis for CMV disease (group 2).Preemptive ganciclovir therapy significantly reduced the incidence of CMV disease (P.05) in CMV-seropositive renal transplant patients who were treated with ALA and was well tolerated. In addition, the cost of prophylactic therapy was offset by the decreased length of hospitalization observed in patients in group 1.Preemptive ganciclovir therapy provides a cost-effective approach toward significantly improving the outcome of renal transplantation in CMV-seropositive patients treated with ALA.

Purification of antilymphocyte antibody (ALA) from patients with systemic lupus erythematosus (SLE) was achieved by immunoabsorption and elution. Human tonsil cells or thymocytes were used as absorbents. Complement dependent microcytotoxicity tests showed that, in comparison to the parent sera, the eluate from tonsil cells was eight times, and that from thymocytes four times, more active. Antinuclear activity was eliminated by elution. The ALA was almost entirely IgM, IgG being involved in only a few cases. IgA lacked cytotoxic activity. ALA was directed at both T- and B-cell surface determinants, which suggests that, in SLE, it has a heterogeneous biological composition.

The cytotoxic activities of individual lupus sera were demonstrated against T gamma cells, T gamma (-) cells and B cells. Immunoglobulin classes were also determined in these antilymphocyte antibodies (ALA) in SLE. T gamma-specific ALA and B-cell-specific ALA were almost equally distributed as regards IgG-dominant type, mixed IgG and IgM type and IgM dominant type, while IgM dominant type was predominant in T gamma (-)-specific ALA. Only the IgG type of T gamma-specific ALA among these ALA was significantly associated with clinical parameters, including hypocomplementemia, elevated immune complex levels and high anti-double-stranded (ds) DNA titres. Serial studies on ALA in a typical case of SLE were performed. Active clinical signs were associated with elevated cytotoxicities of IgG type of T gamma-specific ALA and with relatively low cytotoxicities of the IgM type, whereas after massive corticosteroid therapy, these signs disappeared in tact with the reduction in cytotoxic activities of IgG type of the ALA and the relative rise in cytotoxicities of IgM type of the ALA. These results suggested that IgG class of T gamma-specific ALA seemed to play a major role among several types of ALA in SLE.

Antilymphocyte, antipolynucleotide, and antiviral antibodies in 15 Soviet systemic lupus erythematosus (SLE) probands and their 41 relatives were compared with those in 57 members of 15 control Russian families. Seventy-eight and three-tenths percent of SLE relatives were positive for antilymphocyte antibody versus 26.3% positive reactions in controls. Antipolynucleotide antibody closely paralleled antilymphocyte antibody in both groups. Antiviral antibody was significantly increased in SLE relatives as compared to control family members. No correlation was noted between quantitative IgG, IgA, or IgM levels and various antibodies studied.

Sera from systemic lupus erythematosus (SLE) patients, family members, and normal human donors were found to contain antibodies against surface antigens on peripheral blood lymphocytes from various animals. SLE sera contained high antilymphocyte antibody titers against all animal cells tested, while the normal sera had low titers against mammalian lymphocytes and high titers against lymphocytes from chickens. Sera from family members contained antilymphocyte antibody in titers that differed from normal sera only when the human lymphocytes were used as targets. Absorption with human and chicken lymphocytes indicated that at least two antilymphocyte antibody systems occur in these sera.

An earlier report that there is a high incidence (50 to 60 per cent) of cytotoxic antilymphocyte antibody in the sera of parous ewes is confirmed. This antibody is directed against paternally inherited antigens of the fetus. Antibody could be detected pre partum in four out of 34 primiparous ewes. However, there was no strong association between parity and the incidence of antibody. Antibody was also found in three out of 10 older rams which implies that pregnancy is not the only stimulus for antibody production.

The natural cell mediated cytotoxicities (NCMC) were measured in 4 patients with Sjogren's syndrome (SjS) without complication of connective tissue disease (CTD), 4 patients with SjS associated with CTD other than rheumatoid arthritis (RA), 11 patients with SjS associated with RA, and 29 patients with RA without SjS. All 19 patients with SjS showed significantly suppressed NCMC. In the patients with RA without SjS, NCMC of 21 female cases were rather enhanced when compared with controls, while 8 male patients did not differ from controls. The reduced NCMC in SjS did not seem to correlate with the presence of antilymphocyte antibody (ALA). It is of interest that more accelerated NCMC were demonstrated in the patients with RA receiving gold therapy.

Eighty-seven adult renal allograft recipients were initially treated with cyclosporine-prednisone immunosuppression. Thirty patients experienced no episode of rejection. Antilymphocyte antibody therapy (ALS) was administered to 21 of the 68 recipients of cadaveric donor allografts for either primary allograft dysfunction or acute rejection, and to 6 of 19 recipients of haploidentical, living-related allografts because of steroid-resistant rejection. The cumulative allograft and patient survival for the entire series (follow-up 9-36 months) was 84% and 95%, respectively. This improvement in the rate of successful transplantation can be attributed to the selective addition of ALS therapy to recipients with specific instances of renal allograft dysfunction. In this report, the indications for the use of ALS preparations following prophylactic CsA immunosuppression are reviewed. Experience with the protocols of the ALS administration is also discussed. In selected cases, the administration of either ATG or OKT3 can significantly benefit CsA recipients who experience either primary allograft nonfunction or an epidose of acute rejection.

The effect of SLE serum on Con A induced suppressor T-cell was studied in in vitro Ig synthesis. Active SLE sera containing IgG type of Tγ specific antilymphocyte antibody (ALA) markedly inhibited the supressor T-cell activity, whereas either IgM Tγ specific ALA or any Ig classes of Tγ (-) specific ALA did not significantly affect the suppressor T-cell activity when compared with IgG Tγ specific ALA.Other factors possibly present in SLE sera affecting the suppressor T-cell activity were also examined inin vitro Ig synthesis. Aggregated human IgG as a substitute of immune complexes inhibited Con A induced suppression of IgG synthesis in the dose dependent manner. However, their inhibitory rates were far less from those with active SLE sera containing IgG Tγ specific ALA. Corticosteroid also strongly inhibited Con A induced suppressor T-cell activity, while gel-filtration study of lupus serum revealed that the most inhibitory activity was present in IgG (7S) fraction and the removal of IgG from the sera by anti human IgG coated beads resulted in the loss of the inhibition against Con A induced suppressor T-cell activity. These results suggested that the main inhibitory factors contained in active SLE sera for Con A induced suppressor T-cell activity will be IgG type of Tγ specific ALA and other type of ALA may not contribute significantly. Circulating immune complexes and corticosteroid, if they were contained in SLE sera, seemed to play a minor role for the inhibition of suppressor T-cell activity.

To determine whether antilymphocyte antibody(ALA) of the sera from patients with systemic lupus erythematosus(SLE) plays any role in immune dysregulation, I checked the ALA titers in various diseases by the cytotoxicity test and the correlation between titers of ALA and clinical activities of SLE. ALA was detected in 87.5% the total number of SLE patients, in 100% of them during the acute phase, and its frequency and titer were much higher than in other ALA positive diseases. Concerning the relation between ALA titers and several parameters expressing various clinical stages of SLE, I found that titers of ALA were significantly higher in SLE patients with shaggy and diffuse patterns of antinuclear factor(ANF), high anti-ssDNA antibody activities, hypergammaglobulinemia and low complement levels(CH50). These data show a significant correlation between the titers of ALA and clinical activities in SLE; namely the titer of ALA of sera obtained during the acute phase was significantly higher than those of sera obtained during remission. Moreover, anti-T cell antibodies were detected with high frequency in sera from patients with SLE during the acute phase. These data suggest that ALA plays a pathogenetic role in SLE.

Antilymphocyte antibody prepared by elution from glutaraldehyde fixed thymocytes is cytotoxic and prolongs the life of allogeneic skin grafts in mice. Radioactively labeled antibody is slightly more effective in prolonging skin grafts than the unlabeled material.

Rhesus monkeys were treated with sufficient amounts of rabbit antilymphocyte sera and immunoadsorbent purified antilymphocyte antibody to retain full-thickness skin grafts 23 and 29 days respectively. During this immunosuppressed period hapten-specific cell-mediated immunity was induced in six of seven rhesus monkeys immunized with p-azophenylarsono-N-acetyltyrosine (R-tyr) in complete Freund's adjuvant. These observations suggest that in rhesus monkeys different populations of T cells may be responsible for cutaneous sensitization to antigen and rejection of skin grafts.

Antilymphocyte antibody (ALA) in systemic lupus erythematosus (SLE) was studied using an indirect immunofluorescent technique with air-dried, acetone-fixed lymphocytes. Ninety-four per cent of patients with SLE and 65 per cent of their relatives had ALA. The ALA response in SLE patients involved antibodies of all classes. However, the ALA in their relatives was primarily of the IgM class. Restriction of the class of ALA in asymptomatic relatives is analogous to that seen with anti-RNA antibodies and suggests that the switch to production of autoantibodies of the IgG class may be important in the pathogenesis of SLE.

Recent advances in immunosuppressive therapy have dramatically improved the survival rates for recipients of organ allografts by reducing the frequency of rejection. Cyclosporine, azathioprine, and prednisone for immunoprophylaxis are especially effective. When rejection occurs, the treatment usually includes high doses of oral or intravenous corticosteroids, antilymphocyte globulin, or antithymocyte globulin. A new monoclonal antilymphocyte antibody, OKT3, promises to improve allograft survival rates further.