Long-term related kidney graft survival in high-risk patients after monitored donor-specific transfusion protocol.

Altogether 57 patients were included in the related kidney transplantation program. Forty-four recipients were mixed lymphocyte culture (MLC) negative or slightly positive (SI < 7) against their mother/father donor, and most of them showed Fc gamma RII [erythrocyte antibody inhibition (EAI)] blocking antibody in their sera as the consequence of previous random transfusion. Thirteen patients showed significantly high MLC reactivity against their prospective parent donor (SI > 7) and had no EAI blocking antibody in their sera. The latter group was immunized either by buffy coat or purified platelets obtained from their donor in general two or three times at biweekly intervals. The indication for transplantation of donor-specific transfusion (DST)-treated patients was based on the appearance of EAI antibody and a significant reduction in the MLC reactivity (9 patients). DST patients had 100% kidney graft survival for 5 years and the DST untreated ones 75%. Suggested responsible factors for this observation are the haploidentity in HLA and the induction of suppressive immune regulation by DST.

Association between long-term kidney graft survival and the presence of pre-transplant cytotoxic anti-HLA and/or non-MHC 'Fc gamma RII blocking' (anti-TLX) alloantibody.

One hundred kidney graft recipients were analysed retrospectively with regard to the presence of Fc gamma RII (EAI) blocking or cytotoxic HLA antibody induced by pretransplant transfusion. Previous studies suggested that transfusion induces the production of EAI blocking antibody which may have specificity to TLX/CD46/MCP alloantigens. A superior graft survival (65%/9 yr) was found in the presence of EAI alloantibody compared to graft survival in the absence of this antibody (40%/9 yr). Further analysis showed the following survival rates in relation to the combined appearance of HLA cytotoxic and EAI antibody (EAI positive, HLA negative 67%/9 yr; EAI positive, HLA positive 60%/9 yr; EAI negative, HLA positive 0%/9 yr; EAI negative, HLA negative 40%/9 yr). There was striking low graft failure in the first 6 months in patients with EAI antibody. Taking into consideration that the HLA B/DR mismatching grade in all various groups were the same and no considerable difference was found in association to graft survival, the presence or absence of alpha EAI (anti-TLX) antibody solely seems to have superior or additional effect on graft survival as compared to HLA matching.

The polymorphic human TLX-B/CD46/MCP system and its implications in transplantation and reproduction.

TLX antigens have been found on most peripheral blood cells, trophoblasts, seminal vesicle cells and sperms. These antigens seem to be associated with the membrane cofactor protein (MCP) and the CD46 antigen. Alloantibodies to TLX antigens with Fc tau RII-blocking features were obtained by transfusion of leucocytes or platelets. Preliminary population studies revealed that alloantibodies to TLX/CD46/MCP recognize four overlapping specificities. The terminology TLX-B was introduced with specificities TLX-B1, B2, B3, B4 and frequencies obtained in the population were: 38%, 46%, 42% and 26%, respectively. Family studies showed an independent segregation of the TLX and HLA alleles. At the cellular protein on trophoblast, the alloantibody detected a glycoprotein of 66-67 kDa molecular mass, which may correspond to the alpha chain of the TLX/CD46/MCP isotypes. A direct association of the alloantibody with Fc tau RII could be excluded thus its FcR blocking feature is probably based on an indirect functional effect. After transfusion and in pregnancy the induction of TLX alloantibody production depended on the mismatching in the TLX/CD46/MCP phenotypes. Probable associations were revealed in the case of recurrent habitual abortion between the lack of Fc tau R blocking antibody production and the matched TLX specificities of the couples. After transfusion, TLX alloantibody production with Fc tau R and MLR blocking function was induced only when the recipient was lacking the TLX specificities expressed on the donor cells. Suppression of MLR was found only when TLX specificity in sera corresponded to the TLX specificity of the effector cell. The immunopathological importance of these findings in transplantation and reproductive medicine has yet to be clarified.

Functional and immunogenetic characterization of FcR-blocking antibody.

The characteristics and functional importance of FcR-blocking antibodies and their production were investigated after immunization with whole blood, "buffy coat" and purified platelets. We studied the presence of FcR-blocking antibody in haemodialyzed, transfused patients waiting for kidney transplantation, and we found strong correlation between the blocking effect and better graft survival. We suggest that this blocking antibody does not attack FcR as primary target. Investigation of blocking activity of ten different immune sera on 50 healthy panel cells showed that target antigen has some polymorphic varieties. On basis of family studies it seems that the target antigen is not linked to HLA haplotype. The blocking effect of sera could be removed by absorption of CD8+ cells, B lymphocytes, platelets and granulocytes, but not with erythrocytes, monocytes, CD8- cells and NK cells.

Comparative study of alloimmune reactions induced by leukocyte and platelet transfusions in humans: characteristic changes of activation markers, gamma interferon, and FcR blocking antibody production.

This study was undertaken to define immune responses induced by leukocyte and platelet transfusions. We offer evidence that activation by alloimmunization with intravenously administered "buffy coat" cells results in immune alterations similar to the early rejection episodes following kidney transplantation. Thus, IL-2 and HLA-DR expression increased on PBL 2 and 3 days after antigen exposure and paralleled elevations of IFN-gamma, neopterin, and beta 2 microglobulin levels. No significant changes were detected in the number of T-cell subpopulations. Alloimmunization by purified platelets alone that express only class I MHC antigens failed to induce the above alteration, even after repeated exposure. Repeated alloimmunization with "buffy coat" cells or isolated platelets stimulated a progressive increase up to 100% blocking activity on EA rosette formation. We conclude that the expression of activation markers on PBL and the production of IFN gamma and neopterin reflect the early phase of alloimmune response induced by leukocytes. This type of alloactivation is not a prerequisite for the development of FcR-blocking antibody, which is produced after pure platelet transfusion as well.