Tolerance In Primates Research Articles

Social Tolerance in Chimpanzees Depends on Group Composition: A Longitudinal Study Across Four Communities

Social tolerance in primates has commonly been treated as a stable, species-specific characteristic. Recent research, however, has questioned this position and emphasized the importance of considering intra-species variation in social tolerance. Here, we investigate the temporal stability of social tolerance in chimpanzees using the commonly employed measure of cofeeding tolerance; our results present the first multi-group, longitudinal, experimental assay of cofeeding tolerance in chimpanzees using quantitative methods. Cofeeding tolerance is measured in four groups of neighboring sanctuary-housed chimpanzees over the course of eight years. We pair these experimental data with accessory data on the demographic compositions of the groups to study factors that may influence cofeeding tolerance. We find appreciable levels of variation across both groups and years. We show that most of this variation can be explained by specific demographic variables, such as the number of young infants and the number of juvenile and adolescent females present within a group in a given year. These results imply that social tolerance is a ‘responding trait’ of chimpanzee sociality, reflecting individual- and group-level responses to social and demographic changes. To fully describe intra-species ranges of social tolerance, future research should consider the extent of variation both between groups as well as within groups over time.

Successful Tolerance to Fully MHC Disparate Renal Allografts via Donor Hematopoietic Mixed Chimerism in Non-Human Primates

To the Editor: Rodent studies clearly show that sharing of MHC genes between donors and recipients is regularly associated with improved allograft survival. This is essentially attributed to: (1) reduction of early inflammatory direct T cell responses involved in acute allograft rejection and (2) self-MHC molecules expression on donor cells promoting regulatory immunity. The precise contribution of donor/recipient MHC gene matching to transplant rejection or acceptance in clinical transplantation has been somewhat more difficult to define due to the use of intensive immunosuppression in all human allograft recipients. Nevertheless, most authors agree that improved long-term graft survival is generally expected in patients receiving MHC-matched renal allotransplants. Rodent studies also demonstrate that transplant tolerance is easier to accomplish when allogeneic tissues express some or all of the recipient's MHC proteins. Nevertheless, tolerance of fully allogeneic transplants is regularly achieved in laboratory-bred mice using a variety of procedures including donor specific transfusion, donor hematopoietic chimerism and lymphocyte costimulation blockade. In contrast, such tolerance in primates has proven to be much more arduous due presumably to the presence in these recipients of preexisting alloreactive memory T cells (TMEM). These TMEM undergo differentiation and clonal expansion following previous exposure to alloantigens through blood transfusion, pregnancy, a previous transplantation or via cross-reactivity with microbial antigens. A recent article in AJT by Ramakrishnan et al. 1, referring to a recent report from our group 2, suggested that we had achieved tolerance of renal allografts in non-human primates via mixed chimerism only in highly MHC-matched transplant pairs. This interpretation of our experience is not fully accurate. Indeed, we have reported an inverse correlation between the level of IL-2 and γIFN memory alloreactivity and the degree of MHC class II and I gene sharing among monkey pairs 3. However, this is not an absolutely consistent observation with a substantial number of fully MHC disparate donor–recipient pairs displaying low pro-inflammatory memory responses 3. This suggests that tolerance susceptibility vs. resistance in primates depends primarily upon the frequencies of pre-existing donor-specific TMEM rather than upon donor–recipient MHC matching. In support of this view, we have observed that over one third of the monkeys that became tolerant of renal allografts had actually received a highly MHC-mismatched (>4/6 CyLA mismatches) transplant 4, 5. In summary, the beneficial effects of MHC matching with regards to transplantation tolerance are undeniable. In addition, it is likely that harnessing anamnestic T cell alloreactivity in primates will be essential to successful tolerance of allogeneic transplants across MHC barriers in non-human primates and patients. G. Benichou*, O. Nadazdin, A. B. Cosimi, and T. Kawai Transplantation Research Center, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA *Corresponding author: Gilles Benichou, gbenichou@partners.org The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Overcoming Memory T-Cell Responses for Induction of Delayed Tolerance in Nonhuman Primates

The presence of alloreactive memory T cells is a major barrier for induction of tolerance in primates. In theory, delaying conditioning for tolerance induction until after organ transplantation could further decrease the efficacy of the regimen, since preexisting alloreactive memory T cells might be stimulated by the transplanted organ. Here, we show that such "delayed tolerance" can be induced in nonhuman primates through the mixed chimerism approach, if specific modifications to overcome/avoid donor-specific memory T-cell responses are provided. These modifications include adequate depletion of CD8+ memory T cells and timing of donor bone marrow administration to minimize levels of proinflammatory cytokines. Using this modified approach, mixed chimerism was induced successfully in 11 of 13 recipients of previously placed renal allografts and long-term survival without immunosuppression could be achieved in at least 6 of these 11 animals.

Preclinical and clinical studies on the induction of renal allograft tolerance through transient mixed chimerism

The present review updates the current status of research for induction of tolerance through a mixed chimerism approach in nonhuman primates and humans. Allograft tolerance has been successfully achieved with a nonmyeloablative conditioning regimen and donor bone marrow transplantation in human leukocyte antigen (HLA)-matched and mismatched kidney transplantation. In HLA-matched kidney transplantation, persistent mixed chimerism and renal allograft tolerance has been achieved in some patients. In HLA-mismatched combinations, induction of persistent mixed chimerism has not been achieved using a nonmyeloablative preparative regimen. Nevertheless, the transient mixed chimerism that has been achieved has resulted in long-term renal allograft tolerance in the majority of patients. Recent preclinical studies have demonstrated that the presence of heterologous memory T-cell responses observed in primates, but not in rodents, may be a major barrier for induction of durable chimerism and tolerance in primates. Strategies to overcome such memory T-cell responses may, therefore, be of great value in the development of reliable protocols for clinical tolerance induction. Induction of tolerance in clinical kidney transplantation has been achieved via mixed chimerism approaches. Improvements in the consistency and safety of tolerance induction and extension of successful protocols to other organs and to organs from deceased donors will all be among the next steps in bringing tolerance to a wider range of clinical applications.

Tolerance in xenotransplantation

Purpose of review This review assesses recent progress in the induction of xenograft tolerance, with a focus on the strategies showing promise in preclinical large animal models. Recent findings True xenograft tolerance has been limited to rodent models. In large animal models, T cell costimulatory blockers have been widely used as a key component of immunosuppression in controlling xenograft rejection. Despite significant improvements in xenograft survival, blocking T cell costimulation has not yet shown the ability to achieve tolerance in primates. Development of an effective, nontoxic recipient conditioning regimen allowing donor marrow cell engraftment will be essential to the translation of the mixed chimerism approach to clinical xenotransplantation. Costimulatory blockade has been shown to promote this type of tolerance in rodent xenograft models. Thymic xenotransplantation with Gal-transferase knockout source pigs, for the first time, permitted porcine kidney xenograft survival in nonhuman primates for several months without rejection. Summary Tolerance induction is likely to be critical for clinical success of xenotransplantation. With further investigation, induction of xenotransplantation tolerance may be achieved in nonhuman primates and ultimately in humans.

Durable Donor-Specific T and B Cell Tolerance in Rhesus Macaques Induced with Peritransplantation Anti-CD3 Immunotoxin and Deoxyspergualin: Absence of Chronic Allograft Nephropathy

Tolerance induction can prevent acute kidney allograft rejection without chronic immunosuppression. It is uncertain whether specific tolerance can prevent chronic allograft nephropathy (CAN), which involves both nonimmune and immune injury. This report provides evidence that immunologically tolerant macaques, induced with immunotoxin and deoxyspergualin, developed neither acute rejection nor CAN. Long survivors, bearing MHC-mismatched grafts without chronic immunosuppression for 0.8 to 3.4 years, exhibited general immune competence with donor-specific T and B cell tolerance and no functional or histological evidence of CAN. Stringent criteria for tolerance were satisfied by specific prolongation of donor skin grafts with rapid rejection of third-party skin, followed by indefinite acceptance of a second donor kidney graft and establishment of microchimerism. Primate tolerance with documented absence of CAN may give impetus to the clinical application of tolerance.

Induction of Immunological Tolerance/Hyporesponsiveness in Baboons with a Nondepleting CD4 Antibody

Tolerance induction with anti-CD4 Abs is well established in rodent transplant and autoimmune disease models, but has yet to be demonstrated in non-human primates or in clinical studies. In retrospect, failure of anti-CD4 Abs to induce tolerance in primates may be technical, a consequence of insufficient dosing and Ab properties influencing immunogenicity and cell depletion. To circumvent these possible limitations, we constructed a novel anti-CD4 mAb, TRX1, humanized to reduce immunogenicity and Fc-modified to prevent cell depletion. Using equine immune globulin (equine Ig) as a model Ag, we examined the tolerance-inducing capacity of TRX1 in baboons. During the induction phase, TRX1 inhibited the humoral response to equine Ig in a dose-dependent manner, with complete suppression of response at the highest dose tested (40 mg/kg). Upon challenge, anti-equine Ig responses were generated in baboons treated with 1 and 10 mg/kg doses of TRX1 and in control animals. In higher dosing cohorts (20 and 40 mg/kg), however, the immune response to equine Ig was modulated in seven of nine animals, including complete unresponsiveness to Ag challenges in two animals. Five of nine were hyporesponsive to equine Ig, generating titers 50- to 250-fold lower than control groups. Repeated challenge resulted in titers falling to baseline or near baseline, with two of five hyporesponsive animals becoming unresponsive to Ag. All animals responded to neoantigen immunization, indicating that the modified response to equine Ig was Ag specific. These studies demonstrate that anti-CD4 Ab-mediated, Ag-specific tolerance can be achieved in baboons without long term immune suppression.

Durable donor-specific T and B cell tolerance in rhesus macaques induced with peritransplantation anti-CD3 immunotoxin and deoxyspergualin: absence of chronic allograft nephropathy.

Tolerance induction can prevent acute kidney allograft rejection without chronic immunosuppression. It is uncertain whether specific tolerance can prevent chronic allograft nephropathy (CAN), which involves both nonimmune and immune injury. This report provides evidence that immunologically tolerant macaques, induced with immunotoxin and deoxyspergualin, developed neither acute rejection nor CAN. Long survivors, bearing MHC-mismatched grafts without chronic immunosuppression for 0.8 to 3.4 years, exhibited general immune competence with donor-specific T and B cell tolerance and no functional or histological evidence of CAN. Stringent criteria for tolerance were satisfied by specific prolongation of donor skin grafts with rapid rejection of third-party skin, followed by indefinite acceptance of a second donor kidney graft and establishment of microchimerism. Primate tolerance with documented absence of CAN may give impetus to the clinical application of tolerance.

Transplantation tolerance in primates after total lymphoid irradiation and allogeneic bone marrow injection. III. Lymphocyte responsiveness and suppressor cell activity.

After total lymphoid irradiation (TLI), allogeneic bone marrow (BM) injection, and organ transplantation in baboons, there is a prolonged period of reduced lymphocyte proliferative responsiveness to polyclonal mitogens and allogeneic lymphocytes. The effect observed is greater with the use of fractionated TLI than after single doses of irradiation. Suppressor cell activity can be demonstrated in vitro in most animals by inhibition of mixed lymphocyte reactivity (MLR) by mitomycin-treated recipient lymphocytes harvested after TLI, with or without allogeneic BM injection, and organ transplantation. Preliminary data suggest the presence of both donor-specific and nondonor-specific suppression, although other interpretations are possible, and suppressor phenomena may not be responsible for the transplantation tolerance observed.

Tolerance to type 3 pneumococcal polysaccharide in monkeys.

Rhesus and owl monkeys were injected intramuscularly with 10 to 10,000 γ of Type III pneumococcal polysaccharide. The monkeys were bled weekly, and then reinoculated with the polysaccharide at suitable intervals. The antibody content of their sera was measured by radioimmunoassay and the antigen content of selected sera estimated by the inhibitory effect of the serum upon the capacity of rabbit antisera to precipitate the polysaccharide. Ten γ of the polyeaccharide immunized the monkeys. Ten thousand γ did not immunize them but instead reduced their serum antibody to very low levels. One thousand γ also reduced their serum antibody to very low levels, but not uniformly as far as 10,000 γ. These findings indicate that 1,000 to 10,000 γ of this polysaccharide appear to cause immunologic tolerance in primates.