To obtain an insight into the evolutionary origin of the major histocompatibility complex (MHC) class I polymorphism, a cDNA library was prepared from a heterozygous chimpanzee cell line expressing MHC class I molecules crossreacting with allele‐specific HLA‐A11 antibodies. The library was screened with human class I locus‐specific DNA probes, and clones encoding both alleles at the A and B loci have been identified and sequenced. In addition, the sequences of two HLA‐A11 subtypes differing by a single nucleotide substitution have been obtained. The comparison of chimpanzee and human sequences revealed a close similarity (up to 98.5%). The chimpanzee A locus alleles showed greatest similarity to the human HLA‐A11/A3 family of alleles, one of them being very close to HLA‐A11. Similarly, segments of the ChLA‐B alleles displayed greatest similarity to certain HLA‐B alleles. The calculated evolutionary branch point for the A11‐like alleles is 7 x 10(6) to 9 x 10(6) years, whereas the other A locus alleles diverged between 12 x 10(6) and 17 x 10(6) years ago. Since the human and chimpanzee lineages separated 5 x 10(6) to 7 x 10(6) years ago, our data support the notion that during evolution, MHC alleles are transmitted from one species to the next.
Both treatment protocols prevented rejection for the duration of the treatment in most animals. Blocking costimulation by anti-CD40 or by anti-CD40 plus anti-CD86 may be an effective method to prevent graft rejection and may obviate the need for other immunosuppressive drugs, especially in the immediate posttransplantation period.
Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-β1+ interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-β1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-β1. Peripheral leukocytes from rejecting monkeys lacking TGF-β1+ allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity trans-vivo assays. In contrast, allograft acceptors with TGF-β1+ infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-β1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8+ and CD4+ interstitial T cell infiltrates, but only the CD4+ subset included cells costaining for TGF-β1. Our data support the hypothesis that the recruitment of CD4+ T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.
SummaryType II collagen-induced arthritis (CIA) is an experimentally inducible autoimmune disorder that is, just like several forms of human arthritis, influenced by a genetic background. Immunization of young rhesus monkeys (Macaca mulatta) with type II collagen (CII) induced CIA in about 70% of the animals. One major histocompatibility complex (MHC) class I allele was present only in young animals resistant to CIA and absent in arthritic animals. This strong association suggests that the MHC class I allele itself, or a closely linked gene, determines resistance to CIA. The mechanism controlling the resistance to CIA becomes less efficient in aged animals since older rhesus monkeys, which were positive for the resistance marker, developed a mild form of arthritis. At the cellular level it is demonstrated that resistance to CIA is reflected by a low responsiveness of T cells to CII. This association between a specified MHC class I allele and resistance to an autoimmune disease points at the importance of the MHC class I region in the regulation of the immune response to an autoantigen.
Objective. Collagen-induced arthritis (CIA) in the rhesus monkey is a nonhuman primate model of rheumatoid arthritis (RA). The close phylogenetic relationship between humans and the rhesus monkey makes this model useful for the preclinical safety and efficacy testing of new therapies that are inactive in animals more distinctly related to humans. In this study, we tested the therapeutic potential of a novel, small molecular weight antagonist of CCR5, SCH-X, in this model.Methods. CIA was induced in 10 rhesus monkeys. The animals were allocated to receive SCH-X or saline as the control (n ؍ 5 in each group). Treatment was initiated on the day of CIA induction and continued for 45 days. Monkeys were monitored before and 63 days after CIA induction for macroscopic signs of clinical arthritis, such as soft-tissue swelling and body weight. Furthermore, markers of inflammation and joint degradation were monitored to follow the disease course.Results. Only 2 of 5 animals in the SCH-Xtreated group displayed prominent soft-tissue swelling, compared with all 5 saline-treated monkeys. In addition to the suppression of joint inflammation, treatment with SCH-X resulted in a reduction in joint destruction, as demonstrated by lower rates of urinary excretion of collagen crosslinks, with confirmation by histology. Whereas in all saline-treated monkeys, marked erosion of joint cartilage was observed, this was absent in 4 of the 5 SCH-X-treated monkeys.Conclusion. The systemic effects of treatment with SCH-X were a suppressed acute-phase reaction (reduction in C-reactive protein level) in the 3 treated monkeys with CIA that remained asymptomatic, and an altered antibody response toward type II collagen. The results suggest that the CCR5 antagonist SCH-X might have a strong clinical potential for treatment during periods of active inflammation, as seen in RA.Chemokines are involved in the trafficking, localization, and differentiation of leukocytes, as well as in effector functions (1). Certain chemokines are produced only during conditions of inflammation and are held responsible for the specific attraction of cells toward inflammatory sites. By the selective expression of chemokine receptors on specific T cell subsets, chemokines are believed to contribute to specific features of the inflammation process and the resulting tissue destruction by the attraction of cells with specific functional properties. This is illustrated by the preferential expression of CCR5 and CXCR3 on Th1 cells (2,3) and of CCR4 and CCR3 on Th2 cells (4). In addition to the selective expression on in vitro-generated Th1 cell lines, target organs in Th1-associated autoimmune diseases, such as the central nervous system in multiple sclerosis (MS), the thyroid gland in Graves' disease, and synovial joints in rheumatoid arthritis (RA), are enriched with T cells expressing CCR5 and/or CXCR3 (5-12). Moreover, increased levels of CCR5 and CXCR3 ligands have been detected in areas of inflammation and/or the Drs. Tagat, Steensma, and McCombie hold a patent on SCH...
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