Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.

Presence of CD4, CD8 double-negative and T-cell receptor-gamma-delta-positive T cells in lymphocyte cultures propagated from coronary arteries from heart transplant patients with graft coronary disease.

Previous studies have shown that the interleukin-2-induced propagation of lymphocytes from endomyocardial biopsy specimens, an indicator of cellular rejection, is associated with the development of graft coronary disease in heart transplant patients. To further investigate the concept of cell-mediated immune responses in graft coronary disease, we have applied the methodologies of interleukin-2-induced propagation of lymphocytes from arterial tissues. In a group of 23 patients, which included 6 heart, 6 kidney, and 11 liver transplant recipients, we observed that arterial lymphocyte growth was significantly associated with obliterative vasculopathy (p less than 0.03). T-cell phenotyping analysis of coronary artery-derived lymphocyte cultures from three heart transplant patients with graft coronary disease showed significant numbers of CD4, CD8 double-negative T cells and T-cell receptor-gamma delta cells, especially when the cultures were established with relatively high doses of 400 U/ml of interleukin-2. These data suggest that the subset of CD4-CD8-, T cell receptor-gamma delta+ T cells may play a role in the pathogenesis and progression of graft coronary disease.

Influence of panel-reactive antibody and lymphocytotoxic crossmatch on survival after heart transplantation.

Review of 463 heart transplants was undertaken to examine the relationship between level of panel-reactive antibody (PRA) and a standard donor-specific lymphocytotoxic crossmatch (LXM) on the incidence of death from hyperacute, acute, and chronic rejection. Death from chronic rejection was defined as being caused by graft atherosclerosis. Hyperacute rejection was diagnosed in 18 allografts, and only two recipients had PRA greater than 10% and another two a positive LXM. Five-year actuarial freedom from death caused by all forms of rejection correlated with PRA values as follows: PRA 0% to 10% (415 patients), 85%; PRA 11% to 25% (29 patients), 68%; PRA greater than 25% (19 patients), 57% (p less than 0.005). Additionally, there was a positive linear relationship between PRA and duration of acute rejection episodes in the first 3 months after transplantation. A positive retrospective donor-specific LXM was present in 42 of 401 patients; most of them (32 patients) were low positive (10% to 50% cell death), and none could be correlated with antibody specificity toward donor HLA antigens. Five-year actuarial freedom from death caused by rejection was 83% in those with a negative LXM, 74% in those with low-positive, and 79% in those with high-positive LXM (p = NS). Negative LXM result did not reduce the risk of death caused by rejection in any of the PRA subgroups. While PRA greater than 10% is a risk factor for rejection-related events, a negative LXM in patients with an elevated PRA does not reduce the risk of death resulting from acute or chronic rejection.

Isolation and primary cultures of human intrahepatic bile ductular epithelium.

A technique for the isolation of human intrahepatic bile ductular epithelium, and the establishment of primary cultures using a serum- and growth-factor-supplemented medium combined with a connective tissue substrata is described. Initial cell isolates and monolayer cultures display phenotypic characteristics of biliary epithelial cells (low molecular weight prekeratin positive; albumin, alphafetoprotein, and Factor VIII-related antigen negative). Ultrastructural features of the cultured cells show cell polarization with surface microvilli, numerous interepithelial junctional complexes and cytoplasmic intermediate prekeratin filaments.

Adult rheumatoid arthritis is associated with MC1, a new HLA-D encoded determinant.

We evaluated the association of a new HLA-D encoded determinant, MC1, with adult rheumatoid arthritis (RA). This determinant associates with DR1 and DR4 and can be defined by serological typing. We found MC1 in 83% of 80 patients with RA vs 43% of controls. Although the frequencies of DR1 and DR4 were both significantly increased in patients with RA compared with controls, MC1 had the highest relative risk (6.2) of any HLA-DR antigen tested. MC1 negative and positive populations were not significantly different in any of a variety of clinical and laboratory variables including age, sex, disease duration, age at onset, hours of morning stiffness, functional class, joint count, presence of subcutaneous nodules or bony erosions, frequency of side effects to gold or D-penicillamine, sedimentation rate, and antinuclear antibody.

Immunological factors influencing liver graft survival.

Donor-recipient ABO blood group mismatching is associated with a decreased graft survival rate in liver transplantation. We have been unable to demonstrate an effect of high levels of panel reactive antibody or a positive donor-specific cytotoxic antibody cross-match on graft survival. A limited analysis of HLA-matching for the A, B, and DR loci suggests a paradoxical effect, but much more experience is needed before the true effect of HLA matching on graft outcome can be reliably evaluated.

The definition of ABO factors in transplantation: relation to other humoral antibody states.

The first examples of hyperacute rejection of renal hemografts were seen almost 25 years ago when kidneys were transplanted to ABO incompatible recipients whose plasma contained antigraft isoagglutinins. Hyperacute rejection caused in sensitized recipients by lymphocytotoxic antibodies is similar in that the immune reaction triggers an acute inflammatory reaction that leads to widespread thrombotic occlusion and devascularization of the graft. The events after xenotransplantation between certain species are essentially the same. Potential strategies to avoid the precipitating antigen antibody reaction or to mitigate the resulting effector cascade are described.