C. J. M. Melief

Pretransplantation Blood Transfusion Revisited

BACKGROUND Blood transfusion before organ transplantation has a beneficial effect on allograft survival; the mechanism of this effect has remained a mystery. In murine models, the presence of common histocompatibility antigens in the blood donor and the recipient favors the induction of allograft tolerance. METHODS To investigate the effect of HLA compatibility between blood donor and recipient on the induction of allograft tolerance, we determined the relative frequency of cytotoxic T-lymphocyte precursors specific for donor cells before and at several times after blood transfusion in 23 patients awaiting a first renal transplant. We correlated the results with the presence of shared HLA antigens. RESULTS T-cell nonresponsiveness against donor cells developed after blood transfusion in 10 of the 23 patients. Tolerance developed only if the blood donor and the recipient had one HLA haplotype or at least one HLA-B and one HLA-DR antigen in common (as was observed in 9 of these 10 patients). Tolerance developed relatively late after blood transfusion (one to two months) and was long-lasting. No decline in the T-cell response against donor alloantigens was observed in any of the 13 patients who received transfusions without having HLA-antigen compatibility with the donor. CONCLUSIONS Blood transfusion in which there is a common HLA haplotype or shared HLA-B and HLA-DR antigens induces tolerance to donor antigens. This finding may lead to the development of new strategies with which to induce tolerance for transplantation after blood transfusion. Perhaps transplant donors will be selected not only by HLA-antigen matching, but also on the basis of acceptable HLA-antigen mismatches associated with T-cell non-responsiveness induced by selected blood transfusion.

Anti-H-2 antibodies induced by syngeneic immunization

Alloreactive cytotoxic antibodies were induced in BALB/c mice by syngeneic immunization with normal lymphoid cells. Sixteen out of 41 mice produced antibodies with distinct anti-H-2 specificity. Anti-Kk antibodies were present in all positive sera, but the individual sera produced different reactivity patterns when tested on a panel ofH-2 haplotypes. Absorption and immunoprecipitation experiments confirmed the H-2 specificity of the syngeneic sera.We hypothesize that virus-modified H-2d structures have triggered alloreactive B-cell clones to produce anti-H-2 antibodies.

Transmission of lymphotropic retroviruses (HTLV-I and LAV/HTLV-III) by blood transfusion and blood products

The transmission of lymphotropic retroviruses by blood transfusion and blood product administration causes serious problems for blood (product) supply services around the world. We shall review the evidence that members of the retrovirus family cause adult T cell lymphoma leukemia (ATLL) and acquired immunodeficiency syndrome (AIDS) and can be transmitted by blood transfusion and blood product administration. Current measures to prevent the spread of pathogenic retroviruses by these iatrogenic modes of transmission will be discussed, and future developments expected in this area will be indicated. (HTLV-111) was isolated from the lymphocytes of patients with acquired immunodeficiency syndrome (AIDS) or lymphadenopathy syndrome (6,7]. LAV/HTLV-I11 is an example of a retrovirus which does not malignantly transform its target cells, but rather destroys them, in this case causing immunodeficiency. Other examples of cytopathic retroviruses are the equine infectious anemia virus and Visna virus [8]. A characteristic feature of all retroviruses, reflected in their name, is their capacity to make a DNA copy of the viral RNA with the enzyme reverse transcriptase [9, lo], allowing integration into host cell DNA, a necessary step in the virus replication cycle [ 1 I].

Immune Adherence of Leucocytes and Fibroblasts Derived from Skin, Sensitized by Cytotoxic Leucocyte Iso‐Antibodies and Complement, to the Surface of Indicator Cells

Evidence was found that human lymphocytes and fibroblasts derived from human skin, sensitized by cytotoxic leucocyte iso‐antibodies and complement adhere to the surface of indicator cells. The reaction mechanism showed the characteristics of the immune adherence (I.A.) phenomenon. Experiments made clear that in the I.A. assay the same antibody is detected as in the cytotoxic antibody test, based on dye exclusion. The sensitivity of the I.A. assay was shown to surpass slightly that of the cytotoxic antibody test.

Fine specificity of cytotoxic T lymphocytes directed against H-2Ld.

The fine specificity of cytotoxic T lymphocytes (CTL) directed againstH-2Ld was analyzed by studying the lytic activity of BALB/cH- 2dm2 (H-2Ld loss mutant) anti-BALB/c-H-2d CTL, generated in secondary mixed lymphocyte culture (MLC) against a panel of target cells of differentH-2 haplotypes. Target cells of allH-2 haplotypes tested, except that of the MLC responder, were lysed by anti-Ld CTL, although to a widely varying extent. The genes coding for antigens detected by anti-Ld CTL were mapped to distinct regions in theH-2d,H- 2dm1,H-2q,H-2k, andH-2b haplotypes. The sequence of lysis intensity against the variousH-2 haplotypes and theH-2 regions involved were as follows:Ld,DqLq,Ddm1 Ldm1,Kk,DbLb,r, p, f, s, C3H.OH (KdDkLk), strong lysis occurring againstLd and weak lysis againstH-2s and C3H.OH.By monolayer adsorption and cold target inhibition experiments, it was shown that anti-Ld CTL contained a CTL subset directed against a private Ld specificity, hitherto undetected by anti-Ld antibodies. This subset of CTL was separate from the CTL subsets reacting againstH-2q and against the mutant haplotypeH- 2dm1. The reactions against the latter two haplotypes were also mediated by separate CTL subsets. It is concluded that the Ld molecule, to a varying extent, shares target antigens for CTL with K- and/or D-end H-2 molecules of all haplotypes tested. These antigens are detected by multiple subsets of anti-Ld CTL. One CTL subset is directed against a target structure unique forLd (Ld private specificity).

Demonstration of leucocyte isoantigens on skin cells by means of immune adherence.

Summary. By means of the immune adherence assay it was shown that specific leucocyte isoantigens present on lymphocytes, granulocytes and fibroblasts are also demonstrable on epidermal cells. This suggests that the transplantation antigens of lymphocytes are present on all nucleated cells.

UNEXPECTED LYMPHO‐CYTOTOXIC REACTIONS OF ANTI‐H‐2 SERA ON NORMAL LYMPH‐NODE CELLS: ARE THEY DUE TO ALTERED H‐2 STRUCTURES OR ANTI‐VIRAL ANTIBODIES?

When testing the serum of an individual anti‐H‐2 immunized mouse (B10 x A.SW)F1 anti‐B10.M by the routine micro‐lymphocytotoxicity test on lymph‐node cells, unexpected antibodies were found. The most striking finding was that after absorption of anti‐H‐2.8 antibodies with B10.A(2R) (Kk) cells, antibodies remained which reacted with AKR, B10.AKM and B10.A V + mice while B10.A V‐, B10.BR and C3H mice were negative. While all these strains share the Kk allele, only the positively reacting strains express high titres of infectious RNA turnover viruses. Unexpected reactions were observed also with H‐2d, H‐2j and H‐2r cells and absorption experiments indicated two or three antibody populations.

The Major Histocompatibility Complex (H-2) of the Mouse Influences the Phenotype of Murine Leukemia Virus-Induced Lymphomas

H-2 congenic C57BL mice were inoculated neonatally with a panel of cloned ecotropic and MCF MuLV isolates. Lymphomas were characterized both for their histology and cell surface marker expression. The results indicate: 1) Synergism exists between ecotropic and MCF viruses in lymphomagenesis. 2) A single ecotropic or dualtropic MCF isolate causes a wide variety of T- and B-cell lymphomas. 3) Within a single mouse strain MuLV induced T-cell lymphomas arise earlier than B-cell lymphomas. 4) The H-2 complex influences lymphoma type. 5) The H-2 complex influences penetration of the thymus by thymotropic MCF virus. 6) These H-2 effects are correlated with H-2 linked differences in the immune responses against both MuLV particles and MuLV-infected cells. A model in which the level of the immune response is one of the main factors determining lymphoma phenotype will be discussed.