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Biomedical subjects

T B Strom

Publications and source records attributed to T B Strom.

At least 343 records · Page 19Linked to original sources
PubMed1977

Pathways of complement activation in membranoproliferative glomerulonephritis and allograft rejection.

The complement system is comprised of at least 18 plasma proteins and consists of four functional divisions: two pathways for activation (classical and alternative), a common amplification mechanism for the activating pathways, and a final common effector pathway to which the activating and amplifying sequences are directed. The classical pathway is activated by certain antigen-antibody complexes, while the alternative pathway may be initiated non-immunologically by various microbial polysaccharides. Indeed, mixtures of purified C3, B, D, and P regulated to low-grade interaction by the presence of C3bINA and beta1 H respond to zymosan with amplified C3 and B inactivation. Both pathways form enzymes termed C3 convertases that cleave C3 to generate its major fragment, C3b. C3b interacts with each C3 convertase to permit C5 cleavage in activation of the effector complement sequence, and it interacts with alternative-pathway factors B and D to generate additional C3 convertase, C3bBb, in the amplification pathway. As C3 cleavage represents the most critical step in the elaboration of the biologic effects of the complement system, modulation of this reaction by generation, stabilization, and inactivation of the amplification convertase C3bBb may well determine whether initial activation of the complement sequence eventuates in beneficial or detrimental effects for the host. Initial generation of C3bBb is dependent on prior cleavage of C3, which may occur by the classical pathway or the alternative pathway. Stabilization of C3bBb is achieved with either P or C3NeF after their binding to C3b and C3bBb, respectively. Control of this amplifying step occurs at three levels: intrinsic decay of the inherently labile C3bBb complex, extrinsic decay-dissociation of Bb from the complex by beta1H, and inactivation of C3b by C3bINA. In the presence of stabilizing factors the control proteins must function in sequence, since C3bINA cannot act on C3bBb; beta1H-mediated decay of protective Bb must precede C3b inactivation by C3bINA. C3NeF, which is found in the sera of some patients with MPGN and persistent depressions of serum C3, circumvents all three controls because of its capacity to create a stabilized convertase that is relatively resistant to decay-dissociation by beta1H. The effector complement sequence is activated by cleavage of C3 and C5, which releases vasoactive and chemotactic peptides, C3a and C5a, and generates the major fragments C3b and C5b. C3b, in addition to its function in the amplifying reaction and the C5 convertases, mediates immune adherence to cells possessing membrane-associated receptors for C3b; this in turn promotes the phagocytic and secretory functions unique to each cell type. Cell-bound C5b serves to assemble the cytolytic complex C5b6789, while fluid-phase C5d generates the hemolytically inactive chemotactic complex C567d...

Complement C3↗
PubMed1977

Passive enhancement of rat renal allografts by antibodies to a non-SD (Ag-B) locus analogous to Ia and demonstration of linkage to the MHC.

The rat MHC contains a distinct locus for Ia-like antigens. The alleles of this locus are not always associated with like alleles of the MLR and Ag-B (SD) loci in inbred strains. This is demonstrated by the Fischer strain, which is MLR and tag-B (SD) 1 (H-11) but shares an Ia specificity with BN (Ag-B3, H-1n). The biologic significance of anti-Ia is distinctive, having in vivo graft-enhancing capability, even when it is cross-reacting (i.e., Lew anti-Fi enhances BN). In contrast, anti-AG-B (SD) does not enhance in the rat model.

Animals↗
PubMed1976

The role of nonclassical Fc receptor-associated, Ag-B antigens (Ia) in rat allograft enhancement.

The ability of a hyperimmune Lew anti-BN serum (HIS) to induce enhancement of (Lew/BN)F1 kidneys transplanted into Lew recipients was compared to that of the same antiserum that had been depleted of hemagglutinating anti-Ag-B antibodies by absorption with Brown-Norway (BN) RBC-absorbed sera (RAS) or platelet-absorbed sera (PAS). The RAS and PAS were as effective as the unabsorbed HIS in abrogating early rejection as assessed by renal function and promotion of long-term survival. The absorbed sera retained the capacity to block the mixed lymphocyte culture (MLC) between Lew and BN lymphocytes and to a lesser degree the MLC between Lew and BUF, WF, AUG, and ACI lymphocytes; however, strain specificity was clearly evident at high antiserum dilutions. Similarly, these absorbed sera retained the capacity to block the Fc receptor of BN lymphocytes, and this effect was completely strain specific. In contrast, hemagglutinating and cytotoxic antibodies eluted from platelets used for antiserum absorption did not react with Fc receptors as assessed by rabbit antisheep (IgG)-coated SRBC (EA) rosette formation. F(Ab')2 fragments of PAS also blocked EA rosettes. On the other hand, complement rosettes (EAC) were not inhibited by the HIS. The antibodies were therefore directed against the Fc receptor itself or a structure spatially or functionally closely related to it. Both the Fc receptors and the enhancing capacity of the antisera were strictly specific for the BN genotype. It is suggested that the anti-"Fc receptor" antibody could play an important role in the induction of enhancement by impairing host T-B collaboration as a result of its binding to graft allogeneic "Fc receptors" which appear to be analogous to the major histocompatibility complex (MHC)-coded Ia antigens of the mouse.

Animals↗
PubMed1976

Antibody-dependent lymphocyte-mediated cytotoxicity (Ab-LMC), definition of the "K cell" in the rat.

The nature and membrane characteristics of the "K cell" of antibody-dependent lymphocyte-mediated cytotoxicity (Ab-LMC) were investigated in a widely used rat model of transplantation. Treatment of sensitized effector cell populations with anti-immunoglobulin and complement eliminated K cell cytotoxicity without diminishing the component of T cell-mediated injury. EA and EAC depletion experiments, although demonstrating no loss of K cell cytotoxicity after removal of complement receptor-bearing lymphocytes, produced a marked abrogation of cytotoxicity following the removal of the Fc receptor-bearing lymphocyte pool. Studies on phagocytic properties showed K cell activity to be shared by an adherent as well as a nonadherent cell population. Thus, the Fc receptor emerged as the only constant surface marker of the rat K cell in Ab-LMC.

Animals↗
PubMed1976

Secondary hyperparathyroidism in human kidney transplant recipients.

76 kidney transplant recipients who were up to 4 years post transplant, were studied to assess the incidence of secondary hyperparathyroidism. All patients had good renal function with a mean serum creatinine of 1.4 mg/100 ml. Secondary hyperparathyroidism, as evidenced by increased serum parathyroid hormone levels, was present in 53 of the 76 patients (66%) and radiologic bone disease in 26 of the 76 patients (34%), while hypercalcemia (serum calcium greater than 11.0 mg/100 ml) occurred in only 6 patients (8.5%). The incidence of secondary hyperparathyroidism decreased slightly with time following transplantation, but the degree of secondary hyperparathyroidism as indicated by the levels of serum parathyroid hormone at various times following renal transplantation was essentially similar. The causes for the persistence of this condition are not totally known, but it was found that its incidence was related to the duration of dialysis prior to transplantation.

Follow-Up Studies↗
PubMed1976

Studies on infiltrating host cells harvested from acutely rejecting rat cardiac allografts.

Although the cellular events of rejection of organ allografts have been fully described histologically, little information exists regarding actual mechanisms of graft destruction. Available concepts are based primarily upon assays performed in vitro. This study describes a model designed to correlate such in vitro information with events occurring in vivo within acutely rejecting organ allografts. Infiltrating host cells had been harvested by two techniques from heterotopic cardiac allografts in rats. The various cell classes have been noted and their differential rates of accumulation compared to serial histological observations. Subpopulations of cells have been identified by surface markers, and specific cytotoxicity against donor alloantigen has been determined as a T lymphocyte function. These techniques may be of aid in unraveling the complexities of graft rejection.

Animals↗
PubMed1976

T and B cell patterns in irreversibly rejected human renal allografts. Correlation of morphology with surface markers and cytotoxic capacity of the isolated lymphoid infiltrates.

To define the composition and proliferative and functional activity of the rejection formed sheep erythrocyte rosettes (T cells), expressed surface Ig (B cells) or Fc receptors and specific lymphocyte-mediated cytotoxic activity. Small clumped lymphocytes (48.8 +/- 18.9 per cent) and plasma cells (18.8 +/- 10.9 per cent) were most common and correlated negatively (p less than 0.01). Percentages of surface Ig-bearing and small clumped lymphocytes correlated directly (p less than 0.05) as did the percentages of E rosette-forming and plasma cells (p less than 0.05). The percentages of surface Ig-bearing B cells correlated negatively with E rosette-forming T cells (p less than 0.05). Within this spectrum of rejection, three patterns could be identified. In the first pattern, humoral rejection (by immunofluorescence) was intense and cellular infiltration was primarily by surface Ig and Fc receptor-positive small clumped B lymphocytes. The second and most common pattern consisted of a mixed T and B cell infiltrate with intermediate to high lymphocyte-mediated cytotoxic activity and variable humoral rejection. In the third pattern, invitro studies showed primarily E rosette-forming T cells with paradoxically low lymphocyte-mediated cytotoxic activity. However, morphologic studies also revealed the highest percentages of plasma cells but only mild humoral rejection. Thus, combined morphologic and in vitro studies identified three patterns of protracted renal allograft rejection. Thus, combined morphologic and in vitro studies identified three patterns of protracted renal allograft rejection for which the percentages of plasma cells may provide a distinguishing morphologic marker. Furthermore, the degree of lymphocytic invasion of renal tubules and blood vessels may provide an estimate of lymphocyte-mediated cytotoxic activity.

Antibody Formation↗
PubMed1975

Identity and cytotoxic capacity of cells infiltrating renal allografts.

To determine the identity and cytotoxic capacity of lymphoid cells involved in allograft rejection, we studied viable, monodispersed cells recovered from 10 rejected human renal allografts. A heterogeneous population of cells including macrophages and both bone-marrow (B) and thymus-derived (T) lymphocytes accumulate in rejected grafts. Infiltrating lymphocytes exerted a specific cytolytic effect on 51Cr-labeled peripheral blood lymphocytes bearing donor antigens, ranging from 7 to 44 per cent specific lysis in nine of 10 cases. Cytolysis was closely correlated (r equal 0.91, p less than 0.05) with the histologica grade of cellular rejection but not with humoral rejection, suggesting that cytotoxic lymphocytes are an important element in cellular rejection. Limited fractionation studies showed that both T cells (in early rejection) and non-T cells (in late rejection) may produce cytotoxicity. Since as many as 50 per cent of cells recovered bore Fc receptors, the rejection process may also involve antibody-dependent target-cell lysis.

Animals↗
PubMed1975

Insulin-induced augmentation of lymphocyte-mediated cytotoxicity.

Physiologic concentrations of insulin enhance the ability of cytotoxic lymphocytes to injure target cells. The effect of insulin closely resembles the action of cholinomimetics and guanosine 3',5'-monophosphate upon this system. Since both insulin and cholinomimetics elevate intracellular concentrations of guanosine 3',5'-monophosphate, a common mode of action is suggested.

Animals↗
PubMed1975

Surface properties and functional characteristics of infiltrating cells harvested from acutely rejecting cardiac allografts in inbred rats.

Viable, functioning effector cells exerting donor specific cytotoxic properties have been removed, with their surface properties intact, from acutely rejecting cardiac allografts in rats to define immunological events occurring within the grafts themselves. Macrophages comprised 15 to 25% of the cells harvested; lymphocytes comprised about 75%. A few polymorphonuclear leukocytes (approximately 5%) were present consistently. Lymphocytes bearing surface Ig, B cells, made up 35 to 47% of the mononuclear cells collected. The remaining lymphocytes were presumptive T cells. The surfact attributes of the infiltrating cells were compared to those of cells from recipient peripheral blood, spleen and lymph nodes, and to those from isografted controls. Many of the B lymphocytes possessed Fc receptors but were virtually unable to form erythrocyteantibody complement (EAC) rosettes, in contrast to splenocytes which formed approximately 30% EAC rosettes. Specific cytotoxicity against donor alloantigen-bearing cells, as tested in a 51Cr release assay, was shown to be a T cell function by serial fractionation experiments. Peak cytotoxicity of infiltrating T cells occurred early during the rejection process, while that of cells from recipient blood and lymphoid tissues occurred only following complete graft destruction. Antibody-dependent lymphocyte-mediated cytotoxicity (Ab-LMC) was demonstrated following gentle trypsinization or overnight incubation of the cells. Differing effector cell populations could be distinguished by treatment of anti-Ig and complement; direct donor-specific lymphocyte-mediated cytotoxicity was not disrupted by this treatment, while Ab-LMC was abolished.

Animals↗
PubMed1975

Modification of the rat alloimmune response by enhancing antibodies and the role of blocking factors in the survival of renal grafts.

Correlation of morphological and immunological events ocurring in control and passively enhanced rat renal allograft recipients has revealed an important role for vasculitis in rejection, whereas the tempo and severity of graft lymphocyte infiltration and tubular damage was comparable in both groups during the first 5 days. Thereafter, the degree of cellular infiltration in enhanced allografts progressed and actually exceeded that in control grafts. 2-Mercaptoethanol-sensitive lymphocytotoxic antibodies were present in both groups with comparable titers and appearance times; however, the presence of a severe IgG-containing necrotizing arteritis and glomerulitis in control, but not enhanced, grafts suggests that passive enhancement protects by interfereing with the cooperative T cell-dependent inductive response. Further support for this possibility comes from the fact that the development of cytotoxic lymphocytes against donor target cells was delayed for 48 hr in the enhanced group. While controls died at days 9-11, enhanced animals entered a period of prolonged survival with stable renal function. This state of "autoenhancement" was characterized by a low degree of cell-mediated cytotoxicity and the appearance of serum factors that blocked the in vitro cellular assay. Blocking factors have a low affinity for the attacking cell population, suggesting that they are immune complexes or anti-idiotypic antibodies, and not free alloantibody of high affinity.

Animals↗
PubMed1975

Immunologic enhancement of rat renal allografts. III. Immunopathologic lesions and rejection in long-surviving passively enhanced grafts.

Immunologic enhancement of renal allografts from (Lewis times Brown Norway) F1 to Lewis rats was achieved by administering a single dose of antidonor serum at the time of transplantation. A series of grafts functioning for 1 to 4 months after transplantation were examined by light and immunofluorescence microscopy to evaluate the long-term protective effects of the enhancing serum and to determine if previously unobserved lesions appeared in long survivors. Despite the absence of detectable circulating cytotoxic alloantibody, long-term allografts showed necrotizing glomerular and arterial lesions which resembled those seen in acutely rejecting grafts and were compatible with humoral rejection. Thus, in this model, there is a late decline in the ability of passive enhancement to inhibit humoral rejection. Long-term grafts also developed tubular lesions with deposition of immunoglobulin and complement on the tubular basement membranes (TBM). Anti-TBM antibodies were demonstrated in recipients' sera and found to be organ specific but not major histocompatibility antigen or species specific. This tubular lesion is therefore a unique form of allograft injury in which the immune response is directed against tissue antigen(s) which are distinct from the major histocompatibility antigens that induce rejection.

Animals↗
PubMed1975

The effects of varying dialysis regimens on lymphocyte stimulation.

A protocol was designed to alter mean time average serum concentrations of "middle" (B12) and "small" (urea) molecules. Serum before and after studies was tested for its effect on the blastogenic response to PHA. From this study we have concluded that: 1. Serum of patients on hemodialysis inhibits the mitogenic response of normal lymphocytes to PHA when compared to normal sera. 2. This phenomenon is not responsive to pertubations in dialysis designed to alter the concentration of ""middle'' and ""small'' molecules. 3. The inverse correlation between PHA response and serum PO4 and likewise the inverse correlation with changes in bone X-rays suggest that PTH, fragments thereof, or other factors related to bone and calcium metabolism, could conceivably be involved. This could mediated via cyclic AMP.

Adult↗