S. Surachno

The Size and Phenotype of Virus-Specific T Cell Populations Is Determined by Repetitive Antigenic Stimulation and Environmental Cytokines

Based on the expression of the TNFR SFP CD27, two Ag-primed CD8+ T cell subsets can be discerned in the circulation of healthy individuals: CD27+ T cells that produce a variety of cytokines but do not display immediate cytolytic activity; and cytotoxic CD27− T cells, which secrete only IFN-γ and TNF-α. The mechanism that controls the generation of these different phenotypes is unknown. We show that CMV reactivation not only increases the number of virus-specific T cells but also induces their transition from a CD27+ to a CD27− phenotype. In support of a relation between pool size and phenotype in a cohort of latently infected individuals, the number of Ag-specific CD27− CD8+ T cells was found to be linearly related to the total number of CMV-specific CD8+ T cells. In vitro studies revealed that the acquisition of the CD27− phenotype on CMV-specific T cells depended on the interaction of CD27 with its cellular ligand, CD70. Expression of CD70 was proportional to the amount of antigenic stimulation and blocked by the CD4+ T cell-derived cytokine IL-21. Thus, induction of CD70, which may vary in distinct viral infections, appears to be a key factor in determining the size and phenotype of the CMV-specific T cell population in latently infected individuals.

Cross-reactivity of cytomegalovirus-specific CD8(+) T cells to allo-major histocompatibility complex class I molecules

Background. In transplantation settings, cytomegalovirus (CMV) infection is a common complication. CMV infection is associated with a higher incidence of graft rejection in solid organ transplantation and graft-versus-host disease in bone marrow transplantation. The underlying mechanism of this association could be the generation of CMV-specific CD8+ T cells capable of cross-reacting with alloantigens present on graft and host, respectively. Methods. Whereas as to date, no direct ex vivo analysis can be performed of the CD8+ T-cell repertoire directed at allo-major histocompatibility complex (MHC) class I molecules, virus-specific cells can be readily enumerated by use of MHC-peptide tetrameric complexes. In this study, the authors used this technique to analyze potential overlapping CD8+ T-cell repertoires between self-MHC–viral peptide and allo-MHC complexes by stimulating CMV-specific CD8+ T cells with alloantigens. Results. The authors found that CMV-specific CD8+ T cells are activated and proliferate on stimulation with alloantigens. Conclusions. Although these cells are cytotoxic against CMV-peptide pulsed target cells, no cytotoxicity of CMV-specific cells to alloantigens could be detected, inferring that there are other mechanisms of graft damage by alloantigen-stimulated virus-specific CTL.

The influence of therapy with azathioprine and prednisone on the immune system of kidney transplant recipients

Abstract In a group of 15 kidney-transplant recipients, the effect of maintenance immunosuppressive therapy with azathioprine and low doses of prednisone on cellular and humoral immunocompetence was studied. These patients had undergone transplantation at least 1 year prior to the study and had a stable renal function during the last 3 months. A control group consisted of healthy individuals matching those of the patient group in age and sex. In the patients, the number of T and B lymphocytes in peripheral blood did show a significant decrease. Antibody-dependent lymphocyte cytotoxicity (K-cell function) was depressed. Specific antibody responses after primary and secondary immunization in vivo were not affected, nor was cellular immune reactivity in vitro . However, primary and secondary delayed-type skin reactivity to antigens was severely depressed. From these data, it seems unlikely that these drugs exert their main immunosuppressive effect through inhibition of antigen recognition or of the proliferative phase of the immune response. Rather, their immunosuppressive action in vivo depends on some other mechanism, probably on an anti-inflammatory effect.

Influence of HLA-DRB1* incompatibility on the occurrence of rejection episodes and graft survival in serologically HLA-DR-matched renal transplant combinations

BACKGROUNDnThe aim of the present study was to analyze the effect of HLA-DRB1* mismatches on graft function and graft survival in 92 patients who received serologically HLA-DR split antigen-matched cadaveric renal transplants.nnnMETHODSnThe polymorphic second exon of the HLA-DRB1 alleles was typed using the sequence-specific oligonucleotides technique.nnnRESULTSnThe results show that in 26 of the 92 analyzed combinations, one or more HLA-DRB1* mismatches were found (28%). The analysis of the occurrence of treatable rejection episodes during the first 3 months after transplantation demonstrated a significantly higher incidence of rejection episodes in the HLA-DRB1*-mismatched group: 18 of 26 (69%) in the HLA-DRB1*-mismatched group against 23 of 66 (35%) in the HLA-DRB1*-matched group (P(uncorr)=0.0033). However, no effect of HLA-DRB1* mismatches on graft survival was found, although in general graft survival in the whole patient group was negatively influenced by the occurrence of rejection episodes during the first 3 months after transplantation (P(uncorr)=0.0008). In contrast, in the HLA-DR4-matched donor-recipient combinations (n=28), the effect of mismatching for the HLA-DRB1*04 alleles seemed to have a pronounced effect not only on the occurrence of rejection episodes but also in the form of diminished graft survival.nnnCONCLUSIONSnThus, this study indicates that the existence of HLA-DRB1* allele mismatches in renal transplant recipients, matched for the serologically defined HLA-DR split antigens, is not harmful for the transplant. The exception is the HLA-DRB1*04 mismatch, which seems to be deleterious for the grafted organ.

A longitudinal study on the effects of azathioprine and high doses of prednisone on the immune system of kidney-transplant recipients

Abstract The effects of treatment with azathioprine and high doses of prednisone were studied in five kidney-transplant recipients, from whom blood was obtained prior to and frequently after transplantation during a period of 4 months. Just before initiation of drug therapy, the patients were immunized with hemocyanin and DTP vaccine to elicit primary and secondary humoral immune responses. It was found that the numbers of circulating T and B lymphocytes and also the number of monocytes showed a decrease. In addition, the levels of all serum immunoglobulins except IgM decreased. Primary and secondary antibody responses were normal. In contrast, the proliferative response of lymphocytes in vitro after stimulation with the same antigens was low or even absent. This indicates that, although antigen-reactive cells are apparently depleted from the peripheral blood, they may still be present in other lymphoid compartments. Cytotoxic T-cell function was hardly affected in these patients, but K-and NK-cell activity showed a decrease. From this study we conclude that lymphocytes are redistributed under the influence of therapy with azathioprine and high doses of prednisone, and that this drug regimen has only a small effect on the specific immune reactivity in vivo .

Sequestration of labelled granulocytes in the lungs following administration of OKT3 is dose-dependent

In the present study the consequences of administration of low-dose (0.5 mg) OKT3 for respiratory side-effects and pulmonary sequestration of labelled granulocytes are compared with the known effects of 5 mg OKT3. Ten renal transplant patients were studied, of whom five were treated with 0.5 mg OKT3 and five with 5 mg OKT3. None of the patients in the 0.5 mg group and two of the patients in the 5 mg group experienced dyspnoea. Sequestration of labelled granulocytes in the lungs was significantly lower in the patients receiving 0.5 mg OKT3 compared with the patients receiving 5 mg OKT3. The simultaneously occurring peripheral blood granulocytopenia was significantly more severe in the 5 mg group than in the 0.5 mg group. We suppose that this sequestration of circulating granulocytes in the lungs is at least partly mediated by complement activation products. In vitro it is demonstrated that fixation of complement activation products on peripheral blood lymphocytes depends on the concentration of OKT3 present in the culture medium. We conclude that respiratory side-effects shortly following infusion of OKT3 are related to complement-induced pulmonary leucostasis, the degree of which is dependent on the administered dose of OKT3.

111In-Labelled Platelets in the Diagnosis of Kidney Transplant Rejection

Deterioration of kidney graft function shortly after surgery occurs frequently due to various disorders. Often it may be difficult to differentiate the diagnosis of graft rejection from other complications like acute tubular necrosis, vascular or urological problems or viral infections. A similar problem exists in determining the different types of rejection, i.e. vascular or cellular.