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PubMedDate not supplied

Control of intestinal allograft rejection by FTY720 and costimulation blockade.

INTRODUCTION: The clinical application of small bowel transplantation (SBTx) is hampered by its pronounced immunogenicity. In this study we examined the effects of the novel immunosuppressant FTY720 and costimulation blockade by an anti-CD40L mAb (MR-1) in a stringent mouse model of SBTx. METHODS: SBTx was performed in mice with a full MHC mismatch (donors: C3H=H-2(k); recipients: C57BL/6=H-2(b)). Recipients were divided into four groups: 1, untreated group; 2, MR1 monotherapy (500 microg IV on days 0, 2, 4, and 7); 3, FTY720 monotherapy (1 mg/kg body weight PO for 14 consecutive days after transplantation); 4, FTY720 plus MR1-treated group. Graft rejection grades were assessed by H&E staining. Graft mesenteric lymph nodes (MLNs), Peyer's patches (PPs), as well as intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs) were analyzed by flow cytometry and three-color immunofluorescence staining. RESULTS: Neither FTY720 nor MR1 monotherapy was efficient in preventing the rejection of mouse intestinal allografts, whereas FTY720 plus MR1 profoundly inhibited the rejection response at the 14th posttransplant day. The infiltration of host lymphocytes was reduced in graft MLNs, PPs, IELs, and LPLs by FTY720 therapy. FTY720 plus MR1 inhibited host CD8(+) T-cell infiltration in graft LPLs when compared with grafts treated with FTY720 only. Additionally, two subpopulations, CD11b(+high) Gr1(-) and CD11b(+intermediate) Gr1(+) cells, were decreased in FTY720-treated grafts. CONCLUSIONS: FTY720 plus MR1 efficiently delayed intestinal allograft rejection in a mouse model by preventing the infiltration of host lymphocytes, particularly of CD8(+) cells.

Animals↗
PubMed2006

Multi-array antibody screening in detecting antibodies to mismatched HLA in patients awaiting a second transplant.

Effective identification of HLA specificities to which a prospective transplant recipient has antibodies depends on how effective the most sensitive assay is in detecting these antibodies. To ascertain the assay's efficacy, the results of antibody screening of patients on the waiting list for a second transplant were studied. A commercially available panel of fluoro-coded microbeads coated with multiple and single purified class I or II HLA antigens was used with flow cytometry to detect antibodies in human serum (LABScreen, One Lambda, Canoga Park, Calif, USA). A total of 112 HLA-A, B, and DR mismatches between donors and recipients were present among 34 patients. Antibodies to 56% of the mismatches were detected with 67% of the HLA-A, 38% of the HLA-B, and 63% of the HLA-DR mismatches detected, respectively. Thirty percent of the patients had antibodies to all of the mismatched HLA, 43% had antibodies to some, and 27% did not develop antibodies to any of the mismatched antigens. Among patients who developed antibodies to all of the mismatched HLA, 60% had had a transplant nephrectomy. Only 11% of patients who had no antibodies detected to mismatched HLA had had a transplant nephrectomy and 44% of them were still on immunosuppression. Using the Matchmaker program developed by Duquesnoy, the latter group of patients had a sufficient number of triplet mismatches that could have resulted in an antibody response. All of the undetected antibodies had been identified in other patients in this group. The assay used in this study to detect antibodies is considered the most sensitive one available. Nonetheless, antibodies to slightly less than half of the mismatched HLA antigens were not detected. It appears that the assay system is capable of detecting the antibodies, since in other patients with the same mismatched HLA, antibodies were detected. It is likely that the recipients could develop antibodies since there was a sufficient degree of disparity in the HLA of donors and recipients. Antibodies were more likely to be detected when there had been a transplant nephrectomy and the absence of immunosuppression. There was no way of knowing whether we were missing detecting antibodies or if they were not present. The results of this study have important implications with respect to utilizing "unacceptable antigens" in an allocation system for patients awaiting a second transplant.

Histocompatibility Testing↗
PubMed2002

Distribution of class I and class III MHC antigens in the Tarasco Amerindians.

Class I and class III major histocompatibility complex (MHC) antigen frequencies were analyzed in 130 haplotypes from 33 families belonging to a group of Amerindians culturally and linguistically isolated for more than 12 centuries in Mexico: the Tarascos. The most frequent antigens in this ethnic group of the HLA-A locus are: A2 (gf 0.353), A24 (gf = 0.223), A31 (gf = 0.184), and A28 (gf = 0.161); and the most frequent of the HLA-B locus are: B35 (gf = 0.230), B39 (gf = 0.192), B15 (gf = 0.146), and B5 (gf = 0.123). On the other hand, class III antigens demonstrated relatively high frequencies of the SC31 (frequency = 0.561), SC01 (frequency = 0.076), and SC42 (frequency = 0.069) complotypes. Also important was the relatively high frequency of the HLA-B27 antigen (gf 0.061) and the SC33 complotype (frequency = 0.046), which are either absent or found infrequently in other Amerindian groups. Analysis of MHC haplotypes revealed that four of them have relatively high frequencies, these were the following: [B39;SC31] (11.6%), [B35;SC31] (11.6%), [B15;SC31] (8.0%), and [B5;SC31] (5.8%). Other MHC haplotypes had frequencies lower than 5.0%. The decreased frequency of BF alleles other than BF*S and the presence of the SC33 and SC32 complotypes suggest long time preservation from genetic admixture. This information withstands the basis for population genetic analysis and disease association studies in Mexican mestizos.

Complement C2↗
PubMed2002

Selection of unrelated bone marrow donors by serology, molecular typing and cellular assays.

As compared to hematopoietic stem cell transplantation (HSCT) with HLA genotypically identical donors, phenotypically matched unrelated HSCT is associated with lower survival. Serologically undisclosed HLA disparities account for the increased rate of post-transplant complications. With more than 1300 alleles currently identified, high-resolution molecular typing techniques have to be applied to distinguish the extensive degree of allelic polymorphism of the HLA system. Whereas a HLA-ABDR-serologically identical donor can be identified in the International Registry for >90% of the patients, only half of them can benefit of a highly compatible donor if donor selection is based on allele level matching for HLA-A/B/Cw/DRB1/B3/B5/DQB1 loci. During the last 10 years, we identified only approximately 20% of all known HLA alleles in the searches for our mainly Caucasoid patients. Rare alleles (i.e. alleles that represent <1% of a given serotype) do not have a major impact in patient/donor matching. Most of the incompatibilities are clustered in a limited number of serotypes that can be targeted first during the searches. However, due to linkage disequilibrium (e.g. B-Cw or DRB1-DQB1), incompatibilities at a given locus are often associated with disparities at adjacent loci. In vitro cellular assays such as the cytotoxic T-lymphocyte precursor frequency (CTLpf) analysis may contribute in discriminating functionally relevant HLA class I disparities, as well as minor antigen mismatches in case of sensitized donors. When a rare variant or an uncommon association in the patient's HLA haplotype has been found, the tissue typing laboratory may recommend considering a mismatched donor early in the search procedure instead of continuing a search with a low probability of success.

Alleles↗
PubMed1997

Transplant rejection associated with the presence of human leucocyte antigen antibodies detected by the Fc gamma R inhibition test but not by the lymphocytotoxicity test.

The unselected sera from 869 human leucocyte antigen (HLA) immunized patients awaiting a kidney transplant were analysed using the complement-dependent lymphocytotoxicity test (LCT) with peripheral mononuclear blood cells and the complement-independent immune phagocytosis inhibition test (IPI) with monocytes derived from between five and 10 donors. Sera from 659 patients were LCT and IPI negative when tested against this small panel. Seventy-nine patients had HLA immunoglobulin-G (IgG) antibodies, detectable by the IPI only. Sera from 117 patients had concordantly positive IPI and LCT reactivity with cells from certain donors and concordantly negative IPI and LCT reactivity with cells from other donors (no isolated IPI and no isolated LCT reactions). Fourteen patients had a mixed type of reactivity. Laboratory findings were interpreted along with the transplantation history of the respective patients. Group 1 comprised patients for whom negative results were obtained in both the LCT and the IPI; group 2 patients who were also LCT negative but IPI positive. These two groups showed a significantly different history with respect to the number of irreversible immunological transplant rejections. In group 1, 25.3% of the transplanted kidneys had been rejected whereas in group 2, 56.0% of the kidneys had been rejected (p = 5 x 10(-5)). The high incidence of rejections in the group showing only IPI reactions was comparable with that of group 4 comprising patients with concordant IPI and LCT reactions (59.4%). It is inferred from this retrospective study that renal allograft rejection is associated with the development of IPI reactive antibodies which are not detectable by the LCT. The presence of these antibodies prior to transplantation could be detrimental to the transplanted organ. This being the case, the incidence of transplant failures could be reduced by pretransplant screening using the IPI and by avoiding crossmatch positive donors identified by IPI, especially in patients waiting for a retransplantation.

Antibody Specificity↗
PubMed2000

A PCR-SSP method to specifically select HLA-A*0201 individuals for immunotherapeutic studies.

HLA-A*0201 is an important restriction element for peptide presentation to T cells in disease and cancer. Mutation studies and analyses using cytotoxic T lymphocytes have shown the functional relevance of subtype-specific differences in HLA-A2 molecules for peptide binding and T-cell receptor recognition. Therefore, many immunotherapeutic studies need to accurately select HLA-A*0201-positive individuals. We designed an easy, robust approach based on the polymerase chain reaction using sequence-specific primers (PCR-SSP) to specifically distinguish A*0201-positive individuals from other HLA-A2 subtypes described to date. The first step includes reactions that give information whether the sample donor is HLA-A2 and, if so, whether the individual is homozygous or heterozygous for HLA-A2. Further, it is determined whether the sample has an HLA-A*0209 or an HLA-A*0201 sequence at the corresponding position in exon 4. Samples that may contain an HLA-A*0201 allele according to the results of this first step are subtyped in a second step nested PCR. Here the strategy is focussed on the discrimination of HLA-A*0201 from the other subtypes by considering divergent nucleotide positions in two ways. One SSP combination amplifies the HLA-A*0201 sequence while a corresponding SSP combination specifically amplifies the subtype or group of subtypes differing from HLA-A*0201 at this position. Thus, at relevant polymorphic nucleotide positions the HLA-A*0201 sequence is both directly and indirectly confirmed. This strategy strongly enhances the reliability of the subtyping and allows better verification of HLA-A*0201-positive patient selection for clinical studies.

Alleles↗
PubMed2002

Clinical significance of MHC-reactive alloantibodies that develop after kidney or kidney-pancreas transplantation.

The purpose of this study was to determine the relationships between acute rejection, anti-major histocompatibility complex (MHC) class I and/or class II-reactive alloantibody production, and chronic rejection of renal allografts following kidney or simultaneous kidney-pancreas transplantation. Sera from 277 recipients were obtained pretransplant and between 1 month and 9.5 years post-transplant (mean 2.6years). The presence of anti-MHC class I and class II alloantibodies was determined by flow cytometry using beads coated with purified MHC molecules. Eighteen percent of recipients had MHC-reactive alloantibodies detected only after transplantation by this method. The majority of these patients produced alloantibodies directed at MHC class II only (68%). The incidence of anti-MHC class II, but not anti-MHC class I, alloantibodies detected post-transplant increased as the number of previous acute rejection episodes increased (p = 0.03). Multivariate analysis demonstrated that detection of MHC class II-reactive, but not MHC class I-reactive, alloantibodies post-transplant was a significant risk factor for chronic allograft rejection, independent of acute allograft rejection. We conclude that post-transplant detectable MHC class II-reactive alloantibodies and previous acute rejection episodes are independent risk factors for chronic allograft rejection. Implementing new therapeutic strategies to curtail post-transplant alloantibody production, and avoidance of acute rejection episodes, may improve long-term graft survival by reducing the incidence of chronic allograft rejection.

Acute Disease↗
PubMed1993

Lack of clinical significance of "enzyme-only" red cell alloantibodies.

In a retrospective study on samples from 10,000 recently transfused patients, 35 samples were found to contain an antibody that reacted with ficin-treated red cells but was not demonstrable by low-ionic-strength saline solution and indirect antiglobulin test (LISS-IAT). In those 35 patients, the specificity of the antibody was such that each patient would have been transfused with antigen-negative blood had the antibody reacted in LISS-IAT. Tests on red cells from the units already transfused showed that 19 patients had among them received, by chance, 32 antigen-positive and 74 antigen-negative units. The remaining 16 patients had among them received 57 units that were, again by chance, all antigen negative. One patient given antigen-positive blood suffered a delayed transfusion reaction; in two others the antibodies became LISS-IAT active after transfusion. However, similar changes to the LISS-IAT-active state were seen with two antibodies of patients given only antigen-negative blood. Also found in the 10,000 patients were 28 clinically insignificant antibodies, 77 sera in which the antibody was too weak to identify, and 216 autoantibodies that reacted only with ficin-treated red cells. These data support a belief, generally held in the United States but not necessarily elsewhere, that the use of protease-treated red cells for routine pretransfusion tests creates far more work than the accrued benefits justify.

Clinical Enzyme Tests↗