Anti-idiotypic antibodies and regulation of immune responses.
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Antibodies, Anti-Idiotypic↗
Biomedical subjects
G E Rodey
Publications and source records attributed to G E Rodey.
Anti-idiotypic-like antibodies detected following alloimmunization. Their characterization and relevance to allograft acceptance.
Anti-idiotypic-like antibodies (Ab2) develop during the course of HLA alloimmunization. Several reports indicate that their presence in alloimmunized patients is associated with superior allograft survival, and their appearance correlates inversely with specific HLA antibodies. These features suggest that the induced auto-Ab2 may interact with regulatory idiotypes of HLA-specific antibodies, and may be part of an early immune regulatory mechanism that facilitates the induction of donor-specific immunosuppression. The observations have great potential clinical implications for pretransplant manipulations of the immune response to facilitate donor-specific immunosuppression, and to predict the fate of allografts in previously alloimmunized recipients. Further development and general application of Ab2 testing, however, require better documentation that regulatory immune networks between HLA antibodies and T cells exist, and that improved methods of Ab2 detection that could be used routinely and duplicated in the clinical laboratory, can be developed.
Animals↗
Conclusions: the maintenance of allograft acceptance.
This article summarizes all of the findings of the authors in this issue who examined various laboratory procedures used to implement and monitor transplantation treatment strategies. Histocompatibility matching, crossmatching, monitoring immunosuppression and rejection, and immunologic monitoring of allograft rejection and acceptance are reviewed.
Graft Rejection↗
Characterization of human cardiac-infiltrating cells posttransplantation--functional heterogeneity of anti-idiotype cloned T-cell lines with identical idiotype specificity.
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Antibodies, Anti-Idiotypic↗
Characterization of human cardiac infiltrating cells posttransplantation: II. CD4+ cloned T-cell lines with "anti-idiotype"-like reactivity.
CD4+ T cells were cultured from posttransplant cardiac biopsies placed on irradiated feeder cells of autologous cloned donor major histocompatibility complex class II-specific T-cell lines cultured and grown from previous biopsies. Fourteen of the CD4+ T-cell cultures were expanded and cloned using the same feeder cells. Two of the 14 cloned T-cell lines were examined in detail for their ability to proliferate in vitro. Clones 7E4 and 8G2 proliferated (as determined by primed lymphocyte testing) only when cocultured with a series of distinct autologous cloned T-cell lines from previous biopsies that were specific for donor-specific HLA-DR3 and HLA-DR4, respectively. In addition, when HLA-DR-specific T-cell lines were established using recipient peripheral blood mononuclear cells and a series of HLA-DR-expressing homozygous typing cells, clone 7E4 only responded to the series of distinct HLA-DR3-specific autologous cloned T-cell lines but not to autologous HLA-DR2 and -DR4, and clone 8G2 responded to 3 of 8 distinct autologous HLA-DR4-specific T-cell lines, but not HLA-DR2-specific T-cell lines. These data demonstrate that cardiac biopsies contain CD4+ T cells of recipient origin which show anti-idiotype-like reactivity against T-cell receptors specific for donor-specific major histocompatibility complex class II molecules.
Biopsy↗
Topographic map of the HLA-A2 CREG epitopes using human alloantibody probes.
The topographic architecture of the epitopes expressed on the HLA-A2 glycoprotein using murine monoclonal antibody (mAb) probes indicates at least two sterically distinct domains. Previously, we have demonstrated using human HLA alloantibodies (aAb) that multiple determinants are expressed on each HLA antigen: the highly polymorphic private epitopes and the public determinants that are shared within a family of crossreactive groups (CREG). Our objectives now focus on probing the antigenic structure of the HLA-A2-28-9-B17 CREG using highly specific aAb in conjunction with mAb that have previously been used for structural studies. Both mAb-mediated blockage of complement-dependent cytotoxic aAb and reciprocal antibody (Ab) binding inhibition assays with quantitation by fluorescence flow cytometry have been utilized. We have found that xenogeneic mAb directed against A2-69, A2-B17, and A2-28 crossblock aAb of the same serologic specificity, and vice versa, indicating that the epitopes they respectively recognize are at least in close steric proximity. However, additional HLA-A2, A28, and B17 aAb of private specificity and A2-28-9 aAb of public specificity, for which there are no known mAb counterparts, paint an additional complexity not previously known. We conclude that at least four different alloepitopes can be expressed by each serologically defined HLA antigen. Based on the primary sequence data, we have assigned the location and the amino acid substitutions which most likely account for these discrete epitopes. The unique private determinants are located on the alpha 1 domain together with the interlocus A2-B17 epitope while the public epitopes A2-69, A2-28-9 and A2-28 are located on the alpha 2 domain.
Antibodies, Monoclonal↗
Epitope map of the HLA-B7 CREG using affinity-purified human alloantibody probes.
Monoclonal antibodies (mAb) recognizing the B7 CREG have been used to construct an epitopic map of HLA-B7. Similar studies with human HLA alloantisera have been lacking due to the polyclonal nature of the alloantibodies (aAb). Detergent-solubilized HLA Class I antigens were purified and coupled to activated CH-Sepharose 4B. Sequential affinity isolation of aAb populations using a series of HLA antigen columns enabled us to produce a battery of aAb eluates against both the private B7, B13, B27, and B omega 60 determinants and the public B7-42, B7-60, B7-60-61, B7-27-13-60, B7-42-22-27, B7-8-42-60-41, and B omega 6 epitopes. The topographic relationship of the B7 family of determinants recognized by the Ab probes was derived using crosscompetition Ab blocking assays with quantitation by indirect immunofluorescence and FACS analysis. We have found that aAb and mAb of similar specificity crossblock; Ab of different specificity give complex patterns including both overlapping blocking between the alpha domains and Ab-induced conformational change of the molecule. From these investigations, we conclude that HLA Class I alloantigens bear both multiple, topographically distinct public epitopes and separate private determinants that can be distinguished using human aAb probes. At least four discrete epitopes are expressed by each molecule of the HLA-B7 CREG and can be ascribed to unique aa substitutions on the hydrophilic beta loops of the distal heavy chain domains and also on several exposed areas of the alpha helices. These findings are extremely similar to those of the HLA-A2 CREG and suggest that possibly all Class I molecules possess a comparable, complex degree of serologic polymorphism.
Antibodies, Monoclonal↗
Association of antiidiotypic antibody with successful second transplant of a kidney sharing HLA antigens with the previous hyperacutely rejected first kidney.
The evolution of HLA antibodies and autoantiidiotypic antibodies (AB2) were studied during an 18-month period in a patient who hyperacutely rejected an HLA-A2-positive kidney, but tolerated a second HLA-A2-positive kidney one year later. Following rejection of the first kidney, the patient's serum contained an HLA-A2 antibody that reacted with 100% of HLA-A2-positive panel cells. After several months, the HLA-A2 antibody activity was precipitously lost over a one-month period and could no longer be identified by sensitive lymphocytotoxicity procedures. Approximately one year later, the patient received a second HLA-A2-positive kidney that has survived for a 2-year period and was not associated with significant rejection episodes during the early posttransplantation period. Prior to and episodically following the second transplant, the patient's sera contained antiidiotypic-like antibodies that specifically inhibited HLA alloantibodies directed against HLA-A2. AB2, with specificity for a putative idiotype on HLA-A2 alloantibodies, existed concurrently with other HLA alloantibodies in the patient's serum that had not been lost over the course of several months. This case study demonstrates a temporal association between the loss of a specific HLA antibody and the development of an AB2 with inhibitory specificity for the antibody. The study also confirms that anamnestic responses to donor-specific antigens do not always occur in previously alloimmunized patients rechallenged with the same HLA antigens.
Adult↗
The development and specificity of antiidiotypic antibodies in renal transplant recipients receiving single-donor blood transfusions.
Multiple pretransplant sera obtained from alloimmunized renal transplant recipients were tested for the presence of antiidiotypic-like antibodies (AB2) that inhibit donor-specific HLA antibodies in the microlymphocytotoxicity assay. Fourteen patients received repetitive single-donor blood transfusions (SDT). In this patient group, sera were collected prior to each blood transfusion and prior to transplantation. Three additional patients were studied in whom prior donor-specific HLA antibodies had been lost over a period of 6 months preceding transplantation. Donor-specific AB2-like antibodies were found in the sera of 13/14 SDT patients who did not develop HLA antibodies, and in the 3 patients who had lost donor-specific HLA antibodies. All patients had received prior random blood transfusions in the year preceding the study. Five (38%) of the SDT patients had detectable donor-specific AB2 prior to the initiation of single-donor blood transfusion, presumably related to previous blood transfusions. In the remaining six SDT patients in whom complete serum sets were available, AB2 always appeared after the first blood transfusion. The specificity of HLA antibodies inhibited by AB2 was studied, and antibodies against HLA-A, -B, -C, -DR, and DQw were all identified. Thus, there was no predilection for patients to develop AB2 against locus-specific HLA gene products. This study also confirms the apparent polymorphism of putative crossreactive idiotypes. Approximately 25% of donor-specific HLA antibodies were not inhibited by relevant AB2. This study confirms and extends previous observations that alloimmunization is associated in many patients with the development of antiidiotypic-like antibodies that are capable of inhibiting the binding and cytotoxicity of HLA alloantibodies.
Antibodies, Anti-Idiotypic↗
Nonenzymic glycation of human immunoglobulins does not impair their immunoreactivity.
Diabetic patients have an increased proportion of their immunoglobulins nonenzymically glycated. To investigate the possibility that this may contribute to increased susceptibility to infection, we compared the immunoreactivity of glycated and nonglycated human immunoglobulins against rubella and hepatitis; streptococcal exoenzyme and infectious mononucleosis; human lymphocytotoxic antigens (HLA); and Varicella zoster in terms of antigen-antibody binding, cell agglutination, cytotoxicity, and complement-fixation properties, respectively. We found no evidence to support the supposition that glycated immunoglobulins are functionally impaired.
Antibodies, Viral↗
Positive B cell crossmatches: specificity of antibody and graft outcome.
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Antibodies, Monoclonal↗
Concomitant immunosuppression and donor-specific transfusions prior to renal transplantation.
The induction of immunologic unresponsiveness to improve renal allograft survival was attempted in 151 patients by the pretransplant administration of donor-specific whole blood or buffy coat in conjunction with continuous Aza immunosuppression. All donor-recipient combinations were at least one-haplotype disparate and 21 were two-haplotype disparate. Presensitization was present in ten patients and attempts at desensitization were uniformly unsuccessful. Of the 151 nonpresensitized patients, transient sensitization occurred in 3% and permanent sensitization in 7%. Of 140 nonsensitized patients, 135 underwent renal transplantation from the specific blood donor and 56% have never experienced a rejection episode. The allograft survival rate at two years (93%) and seven years (87%) is significantly better (p less than .01) than our historical experience with one-haplotype living-related transplants at two years (68%) and seven years (59%). The low rate of sensitization (7%) has permitted almost all patients to undergo eventual renal transplantation from the specific blood donor. This and the low rate of early rejection (2%) argues for a modification of the immunologic response, perhaps by clonal deletion, rather than a selecting out process as the mechanism for improved allograft survival.
Azathioprine↗
Renal allograft recipient immunomodulation by concomitant immunosuppression and donor-specific transfusions.
The induction of immunologic unresponsiveness to improve renal allograft survival was attempted in 151 patients by the pretransplant administration of donor-specific whole blood or buffy coat in conjunction with continuous Aza immunosuppression. All donor-recipient combinations were at least one-haplotype disparate and 21 were two-haplotype disparate. Presensitization was present in ten patients and attempts at desensitization were uniformly unsuccessful. Of the 151 nonpresensitized patients, transient sensitization occurred in 3% and permanent sensitization in 7%. One hundred thirty-five of 140 nonsensitized patients underwent renal transplantation from the specific blood donor and 56% have never experienced a rejection episode. The allograft survival rate at 2 years (93%) and 7 years (87%) is significantly better (P less than .01) than our historical experience with one-haplotype living-related transplants at 2 years (68%) and 7 years (59%). The low rate of sensitization (7%) has permitted almost all patients to undergo eventual renal transplantation from the specific blood donor. This and the low rate of early rejection (2%) argue for a modification of the immunologic response, perhaps by clonal deletion, rather than a selecting-out process as the mechanism for improved allograft survival.
Azathioprine↗
Public epitopes and the antigenic structure of the HLA molecules.
Simplified procedures for determining amino acid sequences in proteins and nucleotide sequences in DNA have rapidly expanded the number of MHC molecules for which primary amino acid structure is known. These molecules will be especially valuable as tools to study the structure-function relationships of globular proteins because of the extensive polymorphism of genes coding the MHC genes products. The general three-dimensional structure of class I MHC molecules was recently deduced, but the more subtle topographical microconformations are still undefined. Definition and topographical mapping of epitopes, defined by serological or cellular immune effector products, will be critical probes for these three-dimensional studies. Comparative studies of amino acid sequences among various MHC and molecules have revealed distinct regions of hypervariability in the alpha-1 and -2 domains of class I heavy chains and the alpha-1 and beta-1 domains of most class II molecules. Mutant MHC molecules that differ from each other by no more than one to three amino acids can have structural changes which may result in a loss of the private epitopes that defined the allelic gene product. On the basis of these studies, the private epitopes are thought to be determined by one or more of the hypervariable regions. Similar studies of the relationships between specific regions of the molecule and public epitopes are not fully explored. Because public epitopes are partially conserved structures, one might expect that their structure is not principally determined by hypervariable region. In fact, however, some public epitopes, such as A2/B17 and BW4/Bw6, do map to diversity regions. Epitope mapping as a means of identifying specific topographic sites and relating these sites to specific functional regions of the molecule will be difficult unless the epitopes themselves are better defined. Thus, the capacity to distinguish spatially distinct public epitopes from cross-reactive homologous private epitopes will be important if epitope-specific immunological probes are use to map specific regions of an MHC molecule. Many investigators are interested in the possibility that some components of HLA alloimmunization are regulated through idiotypic networks. Suciu-Foca and colleagues have provided preliminary evidence that epitope-specific HLA alloantibodies bear dominant idiotypic determinants. Antibodies to these determinants appear during pregnancy, following blood tranfusion, and following renal allograft transplantation, also, the antibodies have been correlated with renal allograft survival.(ABSTRACT TRUNCATED AT 400 WORDS)
Antibodies, Monoclonal↗
Preoperative immunomodulation of renal allograft recipients by concomitant immunosuppression and donor-specific transfusions.
The induction of immunologic unresponsiveness to improve renal allograft survival was attempted in 113 patients by the pretransplant administration of donor-specific whole blood or buffy coat in conjunction with continuous Aza immunosuppression. All donor/recipient combinations were at least 1-haplotype disparate and 17 were 2-haplotype disparate. Presensitization, defined as a positive Amos or antiglobulin T cell CM or a positive high-titer (greater than or equal to 1:8) B cell CM was present in 10 patients and not present in 103 patients. Attempts at desensitization of the already sensitized group were uniformly unsuccessful. Treatment of the 103 nonpresensitized patients resulted in transient sensitization in 3 patients, permanent sensitization in 8, and no evidence of sensitization in 92. Ninety-one nonsensitized patients underwent renal transplantation from the specific blood donor, and only 5 have experienced renal allograft rejection loss during a mean follow-up period of 26 months (6 to 70 months). Fifty-four percent have never experienced a rejection episode. The allograft survival rate at 2 years (91%) and 5 years (89%) is significantly better (P less than .01) than our historical experience with 1-haplotype living-related transplants at 2 years (66%) and 5 years (64%). The low rate of sensitization (8%) has permitted almost all patients to undergo eventual renal transplantation from the specific blood donor. This and the low rate of rejection (5%) argues for a modification of the immunologic response rather than a selecting out process as the mechanism for improved allograft survival.
Azathioprine↗
Prediction of crossmatch outcome in highly sensitized dialysis patients based on the identification of serum HLA antibodies.
High levels of allosensitization (greater than 50%), which often occur in dialysis patients awaiting renal transplant, make donor selection difficult. Such patients may be included in elaborate protocols in which they are crossmatched with all available ABO compatible donors, or crossmatching may be deferred until a very-well-matched donor becomes available. The former approach of random crossmatching is costly and inefficient, while the latter approach may overlook crossmatch-compatible donors. We believe that the identification of antibodies present in highly reactive sera and the use of this information in donor selection would increase the frequency of crossmatch-negative donors for these patients. In this study eleven sera, reactive with 70% to 100% of a random cell panel, were obtained from multiply transfused dialysis patients. Sera were analyzed by standard (CDC) and antiglobulin augmented (AHG-CDC) lymphocytotoxicity, and by differential absorption with HLA-typed platelets. All sera contained only one or two antibodies directed against the high frequency public HLA epitopes, accounting for 85% to 100% of each serum's total reactivity. These characterized sera were crossmatched with 114 random normal donors. The frequency of negative crossmatches was 20.5%. However, if the serum antibody data had been used to preselect donors for crossmatch--that is, to exclude donors that were likely to be positive--the negative crossmatch frequency would have increased to 86.4%. The use of the serum analysis data in donor selection would have reduced the total number of required crossmatches by 78%. Serum analysis correctly predicted the outcome of 95.6% of crossmatches performed with an average of 3% false positives and 1.3% false negatives. This approach to donor selection reduces unnecessary crossmatching and increases the likelihood of finding crossmatch-compatible donors for highly reactive patients.
ABO Blood-Group System↗
Blood transfusions and their influence on renal allograft survival.
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Blood↗
Recalcified plasma as nutrient additive in mixed lymphocyte culture.
Animal or human blood protein is a costly but necessary additive to tissue culture. This supplemental protein is provided by the addition of pooled serum or heparinized plasma to standard tissue culture media. Many blood centers store CPDA-1 anticoagulated plasma, a form that does not provide optimal support of mixed lymphocyte culture (MLC). The optimal amount of CaCl2 (1 ml of 1 M CaCl2/100 g) added to citrate plasma and the use of glass vessels result in a completely clotted product that is comparable in MLC support to commercially available pooled human serum. Laboratories that have access to CPDA-1 plasma can replace the growing demand for serum with recalcified plasma without sacrificing quality.
Calcium↗