The role of passenger cells in the induction of allogeneic unresponsiveness to canine renal allografts.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
S Strober
Publications and source records attributed to S Strober.
Attenuation of immunologic memory in canine recipients hyperimmunized with DLA-specific alloantigens.
Explore the source record for details and available documents.
Animals↗
Comparative toxicity of total lymphoid irradiation and immunosuppressive drug treated patients with intractable rheumatoid arthritis.
Outcomes were compared between consecutive patients who had received either total lymphoid irradiation (TLI) or immunosuppressant treatment for intractable rheumatoid arthritis (RA). There were 33 TLI and 32 immunosuppressive recipients; all patients had failed standard therapy. Average followup from the start of therapy was 2.7 years for TLI and 5.9 years for immunosuppressive recipients. Final disability levels were the same in both groups; mortality was equal in both groups as well. There were more hospitalizations for infections in the TLI group and the infecting organisms tended to be staphylococcus or gram negative organisms. Apart from infections, there were more adverse effects reported in the immunosuppressive therapy group.
Arthritis, Rheumatoid↗
The effects of derivatives of histamine on natural suppressor cells.
Histamine is an impressive modulator of immune functions at least via its effects on lymphoid cells. Its in vivo effects will not be used practically as long as they produce the profound cardiovascular and pulmonary effects for which the drug is known. A series of 13 congener derivatives and conjugates of histamine was constructed and was tested to investigate whether chemical alterations would result in pharmacologic actions on leukocytes that were more potent and effect specific than histamine. The new compounds, which contained spacer groups of varying lengths between ligand and carrier and with various aromatic modifying groups, showed potencies widely different from histamine when tested in natural suppressor cells. Some compounds showed selective effects on natural suppressor cells in that they were inactive on myocardial tissue, whereas other compounds were selectively active on the myocardium. Some compounds augmented the suppressive capacity of natural suppressor cells in mixed leukocyte reactions via H1 receptors. Our scheme might be more widely extrapolated to other low m.w. immune modulators in an attempt to make them lymphocyte specific. The data also encourage the in vivo testing of selected histamine analogues as selective modulators of immunity. Some of these modulators might be experimentally useful in vivo because they may lack actions in other tissues.
Adenylyl Cyclases↗
Treatment of NZB/NZW mice with total lymphoid irradiation: long-lasting suppression of disease without generalized immune suppression.
We used total lymphoid irradiation (TLI; total dose = 3400 rad) to treat the lupus-like renal disease of 6-mo-old female NZB/NZW mice. Similar to our past studies, this treatment resulted in a marked prolongation of survival, decrease in proteinuria, and decrease in serum anti-DNA antibodies compared with untreated littermate controls. Although there was no evidence of disease recurrence in TLI-treated mice until after 12 mo of age, the in vitro proliferative response to phytohemagglutinin by NZB/NZW spleen cells recovered within 6 wk such that responses were greater than control NZB/NZW animals. A similar recovery and overshoot after TLI were evident in the primary antibody response to the T cell-dependent antigen sheep red blood cells (SRBC). Both the total and IgG anti-SRBC antibody responses after TLI were greater than those of untreated NZB/NZW controls, and were comparable with those of untreated non-autoimmune mice. Despite this increased response to mitogens and antigens after TLI, we noted a decrease in spontaneous splenic IgG-secreting cells and a decrease in IgG but not IgM antinuclear antibody production. Nonspecific suppressor cells of the mixed leukocyte response were detectable in the spleens of NZB/NZW mice early after TLI. However, the disappearance of suppressor cells was not associated with recrudescence of disease activity. Furthermore, transfer of large numbers of spleen cells from TLI-treated NZB/NZW mice did not result in disease suppression in untreated age-matched recipients. In summary, treatment of NZB/NZW mice with TLI results in a prolonged remission in autoimmune disease, which is achieved in the absence of generalized immunosuppression.
Animals↗
Surface IgG-bearing cells retain the capacity to secrete IgM.
Our previous studies indicated that a large proportion of surface IgG+-primed B cells give rise to clones secreting IgM antibodies. Due to the implications of this result relative to molecular mechanisms of class switching, it was important to document that the surface IgG had been endogenously synthesized by the surface IgG+ cells and was not present as a result of cytophilic IgG. Therefore, spleen cells from immunized mice were treated sequentially with anti-immunoglobulin and protease which removed greater than 99% of surface immunoglobulin. After overnight incubation to allow resynthesis of surface immunoglobulin, the treated cells were sorted for surface IgG-bearing cells and were transferred to carrier-primed, irradiated adoptive recipients for analysis in the splenic focus assay. It was found that the majority of antibody-secreting clones derived from these surface IgG+ B cells still synthesized IgM. These data are discussed relative to current concepts of molecular mechanisms of immunoglobulin class switching.
Animals↗
Effect of total lymphoid irradiation on levels of serum autoantibodies in systemic lupus erythematosus and in rheumatoid arthritis.
The effects of total lymphoid irradiation (TLI) on serum levels of autoantibodies, and of antibodies to diphtheria toxoid, tetanus toxoid, and pneumococcal polysaccharide in patients with lupus nephritis were compared with those previously observed in rheumatoid arthritis (RA) patients. Baseline levels of antibodies to diphtheria toxoid and tetanus toxoid decreased significantly after TLI in patients with lupus and RA, but antibody levels to pneumococcal polysaccharide remained unchanged. After TLI, the levels of antinuclear and anti-DNA antibodies were reduced significantly in lupus, but levels of rheumatoid factor, antinuclear, and antigranulocyte antibodies all tended to increase in RA.
Arthritis, Rheumatoid↗
Regulatory effects of mast cells on lymphoid cells: the role of histamine type 1 receptors in the interaction between mast cells, helper T cells and natural suppressor cells.
We have investigated the role of mast cells as modulators of lymphocyte function because the mast cells are concentrated in the areas of lymphoid storage; they are dependent upon T-cell growth factor for their proliferation; and they appear to be the principle if not sole storage site for histamine. We have tested the influence of mast cells on the proliferation of alloreactive cloned helper T cells, mixed leukocyte reactions, and the suppressive capacity of natural suppressor cells. We used an IL-3-dependent mast cell line that at high numbers (greater than 10(5)) suppressed and at low numbers (10(3) to 6 X 10(4)) augmented the proliferation of TH cells. Addition of histamine to cocultures enhanced the mast cell mediated proliferation of TH cells without directly affecting the helper cells. The action of histamine appeared to be mediated with H1 type receptors on these mast cells. Pretreatment of natural suppressor cells with supernatants from mast cell enhanced their suppressive capability. Here too, histamines enhanced suppression by the NS cell via histamine type 1 receptors on the natural suppressor cells. Our data suggest that mast cells may be a major modulator of the lymphoid cell immune function and demonstrate a role of histamine type 1 receptors in the interaction between mast cells, helper T cells, and natural suppressor cells.
Animals↗
Treatment of autoimmune disease with total lymphoid irradiation. Cellular and humoral mechanisms.
Explore the source record for details and available documents.
Animals↗
Total lymphoid irradiation: basic and clinical studies in transplantation immunity.
Explore the source record for details and available documents.
Animals↗
Treatment of cadaveric renal transplant recipients with total lymphoid irradiation, antithymocyte globulin, and low-dose prednisone.
The ability of preoperative total lymphoid irradiation (TLI) to reduce the need for chronic immunosuppression after cadaveric renal transplantation was examined in 25 recipients who were given a brief course of antithymocyte globulin (ATG) postoperatively with daily low-dose prednisone (0.1-0.2 mg/kg) as the sole maintenance immunosuppressive drug. Patients were selected for the study on the basis of their low levels of cytotoxic antibodies. Grafts were not HLA-matched, and the mean interval between completion of TLI and transplantation was 9 days. During an observation period of up to 25 months, 2 grafts were lost because of rejection. There were two deaths due to disseminated viral infections and two to late cardiovascular complications. At the last observation point, the mean serum creatinine of the 19 patients with functioning grafts was 1.5 mg/dl, and the mean dose of prednisone was 10.2 mg/day. 10 of these patients did not have a rejection episode. Comparison of patients given TLI with a group given cyclosporin at the same institution showed similar graft survival but better graft function in the TLI group.
Adult↗
Cloned natural suppressor cell lines derived from the spleens of neonatal mice.
The establishment and characterization of cloned natural suppressor (NS) cell lines derived from the spleen of neonatal BALB/c mice are described. Cloned NS cells suppress the mixed leukocyte reaction (MLR) between normal adult responder and stimulator spleen cells with a 50-fold greater efficiency than fresh neonatal cells. Suppressive activity of both cells did not depend on the haplotype of the responder or stimulator cells, and was radioresistant. Cloned NS cells did not inhibit the uptake of [3H]thymidine by HT-2 cells proliferating in response to interleukin 2 (IL-2), nor the in vitro secretion of IL-1 by macrophages in response to lipopolysaccharide. Several experiments indicated that absorption of IL-2 could not explain the suppression of the MLR by the NS cells in the range of cell numbers tested. The results suggest that NS cells may suppress the MLR by interfering with early stages of T cell activation. The cell surface of a cloned NS cell line was examined using immunofluorescence staining, and was strongly positive for the Thy-1.2, Ly-5, and asialo-GM1 antigens. However, Lyt-1, Lyt-2, surface Ig, IE, MAC-1, and Fc and C3 receptor markers were not detected. In addition, NS cells showed no cytolytic activity against the YAC-1 target cell line. On the basis of these findings, cloned NS cells do not appear to be mature T cells, B cells, macrophages, or NK cells. The development of cloned NS cells may be useful in determining the identity and mechanism of action of nonspecific suppressor cells in the neonatal spleen, and their role in neonatal tolerance and maternal-fetal relationships.
Animals↗
Efficacy of total lymphoid irradiation in intractable rheumatoid arthritis. A double-blind, randomized trial.
Twenty-six patients participated in a randomized, double-blind study of the efficacy of total lymphoid irradiation in the treatment of intractable rheumatoid arthritis. All 26 patients, for whom therapy with gold compounds and penicillamine had failed, would ordinarily have been considered candidates for cytotoxic or antimetabolite drug therapy. Thirteen patients randomly assigned to receive full-dose total lymphoid irradiation (2000 rad) and 11 patients assigned to receive control low-dose total lymphoid irradiation (200 rad) completed radiotherapy. Alleviation of joint disease activity was significantly greater in the high-dose group as judged by morning stiffness, joint tenderness, and functional assessment (global composite score) at 3 and 6 months after radiotherapy. The high-dose group had a marked reduction in both T-lymphocyte function and numbers, but this finding was not observed in the low-dose group. Complications seen in the high-dose but not low-dose group included transient neutropenia, thrombocytopenia, pericarditis, and pleurisy.
Adult↗
Treatment of intractable lupus nephritis with total lymphoid irradiation.
Ten patients with lupus nephritis and marked proteinuria (3.9 g or more/d) that did not respond adequately to treatment with prednisone alone or prednisone in combination with azathioprine were treated with total lymphoid irradiation in an uncontrolled feasibility study. Within 6 weeks after the start of total lymphoid irradiation, the serum albumin level rose in all patients in association with a reduction in the serum level of anti-DNA antibodies, an increase in the serum complement level, or both. Improvement in these variables persisted in eight patients followed for more than 1 year, with the stabilization or reduction of the serum creatinine level. Urinary leakage of albumin was substantially reduced in all patients. Side effects associated with radiotherapy included transient constitutional complaints in ten patients, transient blood element depressions in three, localized viral and bacterial infections in four, and ovarian failure in one. The results suggest that total lymphoid irradiation may provide an alternative to cytotoxic drugs in the treatment of lupus nephritis.
Adult↗
T cell regulation of the thymus-independent antibody response to trinitrophenylated-Brucella abortus (TNP-BA).
We have previously observed a reduction of the T cell-dependent primary antibody response to dinitrophenylated keyhole limpet hemocyanin, and an enhancement of the T cell-independent response to trinitrophenylated Brucella abortus (TNP-BA) in BALB/c mice after treatment with total lymphoid irradiation (TLI). To elucidate the relative contribution of T and B cells to the enhanced T cell-independent antibody responses after TLI, a syngeneic primary adoptive transfer system was utilized whereby irradiated hosts were reconstituted with unfractionated spleen cells or a combination of purified T and B cells from TLI-treated and untreated control mice. Antibody responses of purified splenic B cells from TLI-treated BALB/c mice (TLI/B) to TNP-BA were enhanced 10-fold as compared with those of unfractionated (UF) spleen cells or B cells from normal (NL) BALB/c mice (NL/UF and NL/B, respectively). Splenic T cells from normal animals (NL/T) suppressed the anti-TNP-BA response of TLI/B by more than 100-fold. NL/T neither suppressed nor enhanced the response of NL/B. On the other hand, T cells from TLI-treated mice (TLI/T) enhanced by 100-fold the anti-TNP-BA response of NL/B, but neither suppressed nor enhanced the response of TLI/B. Thus, T cells can regulate the "T cell-independent" antibody response to TNP-BA. However, experimental manipulation of the T and B cell populations is needed to demonstrate the regulatory functions.
Animals↗
The effects of autacoids on cloned murine lymphoid cells: modulation of IL 2 secretion and the activity of natural suppressor cells.
The pharmacologic effects of histamine and isoproterenol (autacoids) were studied on clones of murine T helper (TH) and natural suppressor (NS) cells. The data are consistent with receptors for the autacoids being nonrandomly distributed on phenotypically and functionally distinct clones. The effects of histamine on IL 2 secretion by TH cells could be either inhibitory or stimulatory, depending on the conditions of incubation with the autacoid. When TH cells were pretreated with histamine, their secretion of IL 2 was augmented; conversely, if histamine was added to the TH cells in the presence of antigen, IL 2 secretion was inhibited. The suppressor function of NS cells was enhanced by preincubation with histamine (10(-4) M) for 4 hr before the washed NS cells were added to responder and stimulator cells in mixed lymphocyte cultures. Two H1 receptor antagonists, mepyramine (10(-6) M) and pyrobutamine (10(-7) M), each competitively blocked the histamine activation of the NS cells, but an H2 receptor antagonist cimetidine (10(-5) M) did not alter the suppressor-enhancing function of histamine. Activation of NS cells did not occur if histamine was added with responder, stimulator, and co-cultured cells in MLR. The effects of each autacoid were additive in cytolytic T cells alone. The adenylate cyclase pools that can be stimulated by isoproterenol and histamine in cytolytic T cells may be independent of each other, but further work will be needed to prove this point.
Animals↗
Natural suppressor (NS) cells, neonatal tolerance, and total lymphoid irradiation: exploring obscure relationships.
Although several laboratories have shown that the appearance of naturally occurring suppressor cells in the spleens of neonatal or irradiated mice is temporarily related to the ease of induction of tolerance, the characteristics of these cells and their regulatory functions have been poorly understood until recently. The experimental data reviewed herein suggests that these cells are related to NK cells with regard to surface phenotype but differ with regard to function. The natural suppressor (NS) cells appear only briefly during the early maturation of the lymphoid tissues but can be induced in adults by manipulation of the lymphoid tissues with certain treatment regimens such as total lymphoid irradiation (TLI). In addition, the NS cells can be propagated and cloned in long-term tissue culture, thereby allowing a more detailed investigation of their properties. The cells have the unique feature of inhibiting the antigen-specific cytolytic arm of alloreactive immune responses but leaving intact the antigen-specific suppressive arm. In this way, alloreactions in the regulatory milieu of NS cells generate large numbers of antigen-specific suppressor cells that can maintain tolerance in vivo. Thus the NS cells may play an important role in the development of host-vs-graft and graft-vs-host tolerance in allogeneic bone marrow chimeras during the "window" of tolerance in which neonate and TLI-treated mice accept the infused allogeneic cells.
Animals↗
Glomerular capillary wall function in human lupus nephritis.
Eighteen patients with nephrotic-range proteinuria due to lupus nephritis were evaluated with a differential solute clearance technique. Renal plasma flow was similar to that in 17 healthy volunteer controls (506 +/- 75 vs. 503 +/- 32 ml/min, P = NS), while oncotic pressure in pre- and postglomerular plasma was depressed by 9.2 and 17.3 mmHg, respectively. These findings are consistent with elevation of net ultrafiltration pressure and suggest that glomerular hypofiltration (51 +/- 9 vs. 103 +/- 8 ml/min, P less than 0.001) was due to a lowered glomerular ultrafiltration coefficient (Kf). In lupus nephritis the fractional clearance of smaller dextrans (radii less than 50 A) was depressed, while that of larger dextrans (radii greater than 50 A) was elevated. A pore model of solute transport, when applied to the dextran filtration data, revealed a subpopulation of large protein-permeable pores in lupus nephritis not present in controls. Moreover, the fraction of glomerular filtrate permeating these enlarged pores correlated directly with the respective fractional clearances of albumin (r = 0.71) and immunoglobulin G (r = 0.75) in individual patients. Immunosuppression in nine patients was associated with an increase of the filtration rate and filtration fraction. Conversely, fractional protein clearances and the area fraction of the glomerular membrane occupied by large pores decreased. We conclude that human immune glomerular inflammation is manifested by a reduction of Kf and increased glomerular porosity and that these membrane alterations are partially reversible.
Adult↗