Co-stimulatory Blockade—A Pathway to Tolerance? (2006)

The ultimate goal in immunotherapy is to develop methods for inducing antigen-specific tolerance that are applicable to patients suffering from autoimmune disease or receiving an organ allograft. Co-stimulatory blockade is a promising experimental approach for inducing antigen-specific tolerance, based on the principle that lack of effective co-stimulation by an antigen-presenting cell not only prevents T-cell activation but may also lead to T-cell anergy or apoptosis. At least 10 distinct co-stimulatory pathways belonging to either the B7:CD28 or TNF:TNF-receptor superfamilies have now been identified. The best characterized are CD28:CD80/86 and CD154:CD40, and numerous studies in rodent models of both autoimmunity and transplantation have demonstrated that blockade of one or both of these positive co-stimulatory pathways may prevent immunopathology and, in many models, induce tolerance (1Larsen CP Elwood ET Alexander DZ et al.Long-term acceptance of skin and cardiac allografts after blocking CD40 and CD28 pathways..Nature. 1996; 381: 434-438Crossref PubMed Scopus (1279) Google Scholar,2Salomon B Bluestone JA Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation..Annu Rev Immunol. 2001; 19: 225-252Crossref PubMed Scopus (937) Google Scholar). The results of blocking a particular co-stimulatory pathway are not always predictable and depend on the nature of the experimental model. This point is highlighted in the report published in this issue of American Journal of Transplantation by Beaudette-Zlatanova et al. on the effects of co-stimulatory blockade in three different BB rat models of autoimmune diabetes (3Beaudette-Zlatanova B Whalen B Zipris D et al. Costimulation and autoimmune diabetes in BB rats. American Journal of Transplantation(in press).Google Scholar). Beaudette-Zlatanova et al. confirmed that blockade of the CD40-CD154 co-stimulatory pathway reduced disease to a varying extent in separate models of spontaneous, induced and recurrent autoimmune diabetes in the BB rat. They also demonstrated that while blockade of CD134-CD134L was ineffective for preventing spontaneous and induced disease, it was highly effective in preventing recurrent autoimmune disease in syngeneic islet transplants. These positive observations are broadly in line with what is already known or might have been predicted. CD40-CD154 blockade has previously been shown to prevent both the onset and recurrence of autoimmune diabetes in the BB rat and CD134, an inducible positive co-stimulatory molecule expressed only by activated T cells, is thought to play a key role in T-cell memory responses and hence blocking interaction with its ligand might be expected to prevent recurrent autoimmune disease (2Salomon B Bluestone JA Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation..Annu Rev Immunol. 2001; 19: 225-252Crossref PubMed Scopus (937) Google Scholar,4Moore WV Chu W Tong PY et al.Prevention of autoimmune diabetes in the DRBB rat by CD40/154 blockade..J Autoimmun. 2002; 19: 139-145Crossref PubMed Scopus (12) Google Scholar,5Kover KL Geng Z Hess DM Benjamin CD Moore WV Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat..Diabetes. 2000; 49: 1666-1670Crossref PubMed Scopus (35) Google Scholar). The surprising finding from the studies reported by Beaudette-Zlatanova et al. is that blockade of the CD28:CD80/86 co-stimulatory pathway using either CTLA4-Ig (a fusion protein that binds with high affinity and blocks both CD80 and CD86) or a combination of anti-CD80/CD86 blocking antibodies not only failed to prevent disease in any of the three experimental models examined but in the BBDP rat accelerated the onset of spontaneous disease. These observations are unexpected in part because CTLA4-Ig is effective in preventing pathology in several other models of autoimmune disease but mostly because CTLA4-Ig prevents spontaneous diabetes in the nonobese diabetic (NOD) mouse (6Lenschow DJ Ho SC Sattar H et al.Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse..J Exp Med. 1995; 181: 1145-1155Crossref PubMed Scopus (571) Google Scholar,7Knoerzer DB Karr RW Schwartz BD Mengle-Gaw LJ Collagen-induced arthritis in the BB rat. Prevention of disease by treatment with CTLA-4-Ig..J Clin Invest. 1995; 96: 987-993Crossref PubMed Scopus (150) Google Scholar). Interestingly, although anti-CD86 prevents disease in the NOD mouse, anti-CD80 blockade alone accelerates the development of diabetes (6Lenschow DJ Ho SC Sattar H et al.Differential effects of anti-B7-1 and anti-B7-2 monoclonal antibody treatment on the development of diabetes in the nonobese diabetic mouse..J Exp Med. 1995; 181: 1145-1155Crossref PubMed Scopus (571) Google Scholar). A possible explanation for both the differential effects of anti-CD80 and anti-CD86 in the NOD mouse, and perhaps also for the acceleration of spontaneous disease following CTLA4-Ig treatment in the BB rat, is a differential effect of co-stimulatory blockade on regulatory and pathogenic T cells. CD28:CD80/86 co-stimulation is known to be important for the expansion and survival of CD4+CD25+ regulatory T cells (8Boden E Tang Q Bour-Jordan H Bluestone JA The role of CD28 and CTLA4 in the function and homeostasis of CD4+CD25+ regulatory T cells..Novartis Found Symp. 2003; 252: 55-63Crossref PubMed Google Scholar). CD80/86 are also ligands for CTLA4, which is a negative T-cell regulatory molecule and their blockade by CTLA4-Ig may impair tolerance by interrupting the CTLA4:CD80/86 inhibitory pathway, adding yet another layer of complexity to co-stimulatory blockade. Beaudette-Zlatanova et al. conclude from their findings that a combination of anti-CD134L and anti-CD154 may prove effective for inducing tolerance to islet allografts in humans with type I diabetes. This is an attractive idea but may be unduly optimistic. Rodent models give only limited therapeutic insights into human autoimmune disease and the extent to which any of the established rodent models of autoimmunity, including the NOD mouse and BB rat models of diabetes, truly reflect their autoimmune counterparts in humans is unclear. As in the case of BB rats, most animal models of autoimmunity are relatively short-term studies conducted in specific pathogen-free rodents, often selected on the basis of their genetic background for their susceptibility to a particular autoimmune disease. Human autoimmune disease on the other hand occurs in individuals of widely varying genetic backgrounds, is often chronic in nature, and occurs in a more aged immune system that has been exposed to a variety of infectious agents and other environmental influences over a period of years. It is not surprising, therefore, that success in identifying effective immune interventions for autoimmunity in animal studies contrasts sharply with the failure of most immune interventions to treat autoimmune disease in humans. There have been some notable successes, perhaps best exemplified by TNF blockade where efficacy was initially demonstrated in the mouse model of collagen induced arthritis and then successfully translated into clinical treatment of rheumatoid arthritis and a number of other autoimmune diseases (9Williams RO Feldmann M Maini RN Anti-tumor necrosis factor ameliorates joint disease in murine collagen-induced arthritis..Proc Natl Acad Sci USA. 1992; 89: 9784-9788Crossref PubMed Scopus (952) Google Scholar,10Feldmann M Steinman L Design of effective immunotherapy for human autoimmunity..Nature. 2005; 435: 612-619Crossref PubMed Scopus (240) Google Scholar). However, there are many other examples where agents such as anti-CD4 mAbs, that prevent a number of autoimmune diseases in rodents, appear disappointingly ineffective in the treatment of human autoimmune disease (10Feldmann M Steinman L Design of effective immunotherapy for human autoimmunity..Nature. 2005; 435: 612-619Crossref PubMed Scopus (240) Google Scholar). Evidence on the efficacy of co-stimulatory blockade in the treatment of autoimmune disease and prevention of organ allograft rejection in humans is limited mainly to blockade of the CD28:CD80/86 co-stimulatory pathway using CTLA4-Ig. Repeated administration of CTLA4-Ig in patients with rheumatoid arthritis ameliorates disease and it is currently undergoing phase II/III trials in rheumatoid arthritis, psoriasis and multiple sclerosis (10Feldmann M Steinman L Design of effective immunotherapy for human autoimmunity..Nature. 2005; 435: 612-619Crossref PubMed Scopus (240) Google Scholar,11Teng GG Turkiewicz AM Moreland LW Abatacept: A costimulatory inhibitor for treatment of rheumatoid arthritis..Expert Opin Biol Ther. 2005; 5: 1245-1254Crossref PubMed Scopus (32) Google Scholar). A high affinity variant of CTLA4-Ig has also shown promise as an alternative to calcineurin blockade for preventing acute renal allograft rejection in a phase II clinical trial (12Vincenti F Larsen C Durrbach A et al.Costimulation blockade with belatacept in renal transplantation..N Engl J Med. 2005; 353: 770-781Crossref PubMed Scopus (755) Google Scholar). Co-stimulatory blockade in these settings, however, is being used as a selective immunosuppressive agent rather than an agent for inducing antigen-specific tolerance. For the time being, at least, this seems likely to remain the case, despite the efficacy of co-stimulatory blockade in rodents for inducing tolerance. Research in the authors’ laboratories is supported by the British Heart Foundation and the Wellcome Trust.