B.A. Bradley

Results of allogeneic bone marrow transplants for leukemia using donors other than HLA-identical siblings.

PURPOSE To compare outcomes of bone marrow transplants for leukemia from HLA-identical siblings, haploidentical HLA-mismatched relatives, and HLA-matched and mismatched unrelated donors. PATIENTS A total of 2,055 recipients of allogeneic bone marrow transplants for chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL) were entered onto the study. Transplants were performed between 1985 and 1991 and reported to the International Bone Marrow Transplant Registry (IBMTR). Donors were HLA-identical siblings (n = 1,224); haploidentical relatives mismatched for one (n = 238) or two (n = 102) HLA-A, -B, or -DR antigens; or unrelated persons who were HLA-matched (n = 383) or mismatched for one HLA-A, -B, or -DR antigen (n = 108). HLA typing was performed using serologic techniques. RESULTS Transplant-related mortality was significantly higher after alternative donor transplants than after HLA-identical sibling transplants. Among patients with early leukemia (CML in chronic phase or acute leukemia in first remission), 3-year transplant-related mortality (+/-SE) was 21% +/- 2% after HLA-identical sibling transplants and greater than 50% after all types of alternative donor transplants studied. Among patients with early leukemia, relative risks of treatment failure (inverse of leukemia-free survival), using HLA-identical sibling transplants as the reference group, were 2.43 (P < .0001) with 1-HLA-antigen-mismatched related donors, 3.79 (P < .0001) with 2-HLA-antigen-mismatched related donors, 2.11 (P < .0001) with HLA-matched unrelated donors, and 3.33 (P < .0001) with 1-HLA-antigen-mismatched unrelated donors. For patients with more advanced leukemia, differences in treatment failure were less striking: 1-HLA-antigen-mismatched relatives, 1.22 (P = not significant [NS]); 2-HLA-antigen-mismatched relatives, 1.81 (P < .0001); HLA-matched unrelated donors, 1.39 (P = .002); and 1-HLA-antigen-mismatched unrelated donors, 1.63 (P = .002). CONCLUSION Although transplants from alternative donors are effective in some patients with leukemia, treatment failure is higher than after HLA-identical sibling transplants. Outcome depends on leukemia state, donor-recipient relationship, and degree of HLA matching. In early leukemia, alternative donor transplants have a more than twofold increased risk of treatment failure compared with HLA-identical sibling transplants. This difference is less in advanced leukemia.

The importance of H-Y incompatibility in human organ transplantation.

SUMMARY As an extension of our first observation in which the peripheral blood lymphocytes of an aplastic amaemia patient with a transplant were able to show HLA-restricted H-Y killing in a cell-mediated lympholysis assay, we report here a second case showing exactly the same phenomenon. A multitransfused woman suffering from aplastic anaemia was shown to have in vitro killing after priming her lymphocytes with her HLA-identical brother. This killing was directed to all male target cells carrying the HLA-A2 antigen. Marginally, killing was also directed to some HLA-A2 female target cells, but this was at a considerably lower level than that directed to male cells. The level of HLA-restricted H-Y killing declined with time. However, it was possible to reactivate the H-Y specific killing by in vitro stimulation with lymphocytes from an HLA-A, -B, and -C-identical, but HLA-D-different male donor. That these findings could be relevant for renal transplantation was supported by renal allograft survival data obtained at 2 years after transplantation. Male allografts from HLA-A2-positive donors in A2-positive females survived for a significantly shorter time than non-A2 male kidneys in non-A2 female recipients. This was only apparent in recipients who produced antileukocyte antibodies.

The effect of antithymocyte globulin on abnormal lymphocyte transformation in patients with aplastic anemia.

Together with Dr. E. Gluckman (Hopital St. Louis, Paris) and Dr. B. Speck (Kanton Hospital, Basel) we have recently published a study, in which the effect of ATG on the clinical course of severe aplastic anemia was assessed [13]. Our conclusions were that: a) about half of the patients suffering from severe aplastic anemia improved significantly after 4 daily doses of ATG; b) it was unlikely that this apparent beneficial effect of ATG was due to patient selection in the sense that we had selected patients which without ATG treatment would have survived anyhow; c) it was possible that the ATG removed from the bone marrow T cells which interfered with the differentiation of the stem cells. A possibility which is strongly supported by in vitro studies by one of us [8] and others [1].

Recent Developments in Histocompatibility Testing in Bone Marrow Transplantation

One of the main goals in histocompatibility research ought to be the identification of non-HLA loci important in graft-versus-host disease (GvHD) and graft rejection. Even if this were achieved, it would only help the clinician identify those patients with HLA-identical siblings who have a minimal risk of GvHD or graft rejection. Although an important contribution, it would not solve the problem of what to do for those patients who do not have an HLA-identical sibling donor who is also identical at these non-HLA loci. In fact, with increasing selectivity based on better typing, the number of these problem patients increases. For such patients who have no related donor, help could come from two directions: 1. The use of unrelated donors compatible for HLA and non-HLA loci. However, we need to know whether matching for HLA between unrelated donor-recipient pairs can reach the same degree of compatibility as that between siblings. 2. More effective immunosuppression.

THE TYN-PLOP PHENOMENON IN HLA-D TYPING

Publisher Summary This chapter highlights different aspects of the TYN–PLOP phenomenon in HLAD typing. The only way to type for HLA-D gene products has been the mixed lymphocyte reaction using homozygous typing cells. In the primed lymphocyte test (PLT), lymphocytes are specifically sensitized to one HLA-D determinant and then used as test reagents. This method is used to raise reagents that are specific for the unidentified HLA-D specificities. The non-HLA-D gene products might in some cases be capable of causing high stimulation, thus, camouflaging the HLA-D compatibility between a typing cell and a responder. More accurate estimations of gene frequencies can be obtained by PLT.