Induction of Immune Tolerance in Islet Transplantation

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1		Naoya Sato	+ 2036 word(s)	2036	2021-11-25 06:54:32	\|
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This entry is adapted from the peer-reviewed paper 10.3390/jcm10225306

Allogeneic islet transplantation has become an effective treatment option for severe Type 1 diabetes with intractable impaired awareness due to hypoglycemic events. Although current immunosuppressive protocols effectively prevent the acute rejection associated with initial T cell activation in recipients, chronic rejection has remained an obstacle for achieving long-term allogeneic islet engraftment.

islet transplantation tolerance induction

1. Introduction

Allogeneic pancreatic islet transplantation has been established as an effective option for severe Type 1 diabetes with intractable impaired awareness due to hypoglycemic events. Islet transplantation involves the intrahepatic delivery of donor-isolated islet cells that supplement insulin production, promoting the recovery of endogenous insulin secretion. Evidence has shown that the development of established immunosuppression protocol has improved outcomes of allogeneic islet transplantation ^[1]. However, the Collaborative Islet Transplant Registry data collected from islet transplant centers around the world reported 1- and 3-year insulin-independence rates of 71% and 24%, respectively ^[2]. A majority of islet transplant recipients return to some form of exogenous insulin usage within a few years of transplantation ^[3]. One factor associated with the long-term outcomes of transplanted islets is chronic rejection. Although current immunosuppression regimens effectively prevent acute rejection, which can suppress initial T cell priming by the donor antigen ^[4]^[5], no established immunosuppressive regimen has been effective in controlling chronic rejection.

When considering the adverse effects of immune suppression, some immunosuppressive drugs can be toxic to islet grafts ^[6], which could worsen the long-term functioning of the transplanted islets. Moreover, the long-term mediation of immunosuppressive drugs has also been associated with increased risk of infections ^[7], malignancies ^[8], cardiovascular disease ^[9]^[10], renal failure ^[11], de novo diabetes ^[12]^[13], and neurotoxicity ^[14]. With the increase in transplantation cases, a growing number of chronically suppressed transplant recipients struggle with such burdens.

The development of donor-specific immune tolerance to an allograft is the ultimate goal of any transplantation given its ability to possibly resolve chronic rejection and disregard the need for maintenance immunosuppression. Inducing donor-specific tolerance in animal transplantation models has been met with several challenges. Nonetheless, the accumulation of information has allowed the recent emergence of several key insights for operational tolerance induction, including the role of regulatory B cells (Bregs) for inducing or maintaining immunological tolerance.

As recently as 2019, Sigh et al. reported on a breakthrough in the tolerance induction protocol for allogeneic islet transplantation in non-human primate (NHP) models ^[15]. This approach for inducing donor-specific tolerance is unique in that it involves the strategic exposure of the recipient to donor antigens prior to transplantation. Several rodent models of allogeneic or xenogeneic transplantation have been evaluated on the impact of apoptotic donor lymphocyte infusion prior to transplantation on graft survival. The achievement by Sigh et al. represents a considerable step forward in the development of immune tolerance induction for human clinical applications.

2. General Understanding of the Relationship between the Immune System and Immunological Tolerance

The immune system can learn to discriminate between the self and nonself via a complex set of central and peripheral immune tolerance mechanisms. When considering immunological tolerance to the allograft, the high proportion of MHC alloreactive T cells, which generally range from 5 to 10% ^[16], has been considered as the main hindrance toward tolerance induction. Regarding T cell tolerance, central tolerance refers to the deletion of reactive clones within the thymus during negative selection. Peripheral T cell tolerance encompasses several mechanisms that take place outside the thymus, including peripheral deletion, anergy/exhaustion, and suppressive function of regulatory T cells (Tregs) ^[17]. The key lies in determining how to apply this mechanism of immunological tolerance, which is inherent in the body system, to induce donor-specific immune tolerance in transplantation.

During the immune destruction of the islet graft, the initial process of rejection is characterized by a rapid infiltration of innate immune cells to the grafts, which can be followed by an antigen-specific T cell response. The established immunosuppression protocol incorporating T cell depletion or anti-TNFa monoclonal antibodies could achieve T cell activation in allogeneic islet transplantation, which contributes to enhancing short-term graft survival ^[1]. However, the current protocol has been considered insufficient for controlling the humoral immune response, including antibody-mediated rejection, which is a significant mechanism of chronic allograft failure ^[18]. Indeed, B cells are known to mainly contribute to humoral immunity and boost cellular immunity. However, several experimental models have shown that B cell subsets ameliorate inflammation and autoimmunity disease, suggesting their capability for regulatory function, namely Bregs. Numerous bodies of evidence have indicated that B cells play essential roles in alloimmunity, including differentiation into antibody-producing plasma cells, sustaining long-term humoral immune memory, serving antigen-presenting cells (APCs), organizing the formation of tertiary lymphoid organs, and secreting pro- and anti-inflammatory cytokines (IL-10) ^[19]. Thus, therapeutic options targeting T cell–B cell interactions are of interest in the development of immunosuppressive protocols for transplantation ^[19]. Although a detailed description of B cell function in transplantation immunity is beyond the scope of the current paper, the following section summarizes exciting evidence obtained from islet transplantation animal models, demonstrating the significance of B cell functions in inducing and sustaining immunological tolerance.

3. Operative Tolerance Induction Using Low-Affinity TIM-1 mAb in an Islet Transplantation Model

TIM-1, which was initially reported to be a T cell costimulatory marker, is a member of the T cell immunoglobulin and mucin domain family of costimulatory molecules. However, an in vivo mice study by Ding et al. showed that TIM-1 was constitutively expressed on B cells rather than T cells and that 6–40% of TIM-1+ B cells express IL-10, including transitional, marginal zone, and follicular B cells ^[20]. Thus, reports have shown that TIM-1 is an inclusive marker of IL-10 + B cells. A mouse model of islet transplantation found that treatment with low-affinity anti-TIM-1, which has functional properties in the Breg development of recipients, leads to significantly prolonged islet allograft survival (approximately 30% of mice achieved long-term engraftment over 100 days) ^[20]. Interestingly, treating B cell-depleted recipients with anti-TIM-1 significantly enhanced IFN-g and ultimately prevented the commonly observed increase in Th2 cytokines. Therefore, B cells are required for anti-TIM-1-induced Th2 cytokine expression.

Moreover, a mouse islet allograft model found that anti-CD45RB antibody in combination with anti-TIM-1 antibody had a synergistic effect in inducing tolerance in all recipients. The dual antibody treatment significantly expanded regulatory B and T cells depending on the presence of recipient B cells with IL-10 activity ^[21]. Using B cell-deficient recipients or depleting B cells with anti-CD20 antibody abrogates the anti-CD45RB-induced tolerance following anti-TIM-1 dual antibody treatment. After exploring the reason why B cell depletion prevented the effects of dual antibody treatment on graft survival, the aforementioned study demonstrated that CD19 + CD5 + CD1d + B10 cells might play an important role only in early-stage transplantation tolerance induction following treatment. Additionally, the study also concluded that CD19 + TIM + B cells might play crucial roles in the whole process of tolerance induction and maintenance. These findings may explain why B cell depletion inhibited the effects of dual antibody treatment.

4. Important Evidence for Inducing Donor-Specific Tolerance to Preclinical Implementation

Although several promising approaches for tolerance induction in a rodent model of transplantation have been reported, as discussed earlier, very few have been translated to human or NHP transplantation models. Unlike laboratory mice, NHPs and humans already have a large collection of memory T and B cells at the time of transplantation. Heterologous immunity or the cross-reactive immune response has the potential to be alloreactive. For instance, up to 45% of anti-CMV T cell clones have been reported to be alloreactive ^[22]. Existing cross-reactive memory immune cells have been a significant hindrance to immunological tolerance in large animals or humans. Thus, tolerance induction in NHPs or humans would be more challenging than that in rodent models, partly due to cross-reactive memory T or B cells. Nevertheless, a few encouraging approaches have led us to believe that immunological tolerance can eventually be achieved in humans, such as mixed chimerism using hematopoietic cell transplantation ^[23]^[24] or ADL exposure ^[15].

One of the most advanced approaches for sustained tolerance is the use of hematopoietic cell transplantation to achieve durable chimerism, where the donor and recipient hematopoietic cells coexist at levels detectable by flow cytometry ^[24]^[25]^[26]. The central feature of the mixed chimerism-based transplant tolerance involves the intrathymic deletion of donor-reactive T cells by irradiation and/or anti-thymocyte globulin ^[27]. One study on kidney transplantation in NHPs reported that this protocol successfully promoted operationally sustained mixed chimerism in conditioning recipient and long-term engraftment ^[23]. Additionally, this approach has been successfully translated to both human leukocyte antigen-matched and -mismatched human renal transplant recipients with immunosuppression-free graft survival ^[24]^[28]. These results encourage attempts at extending this regimen to islet transplantation. Oura et al. reported the results of the mixed chimerism-based tolerance induction in islet transplantation in an NHP model, in which recipients were treated with a nonmyeloablative condition regimen that included total body irradiation, horse anti-thymocyte globulin anti-CD154 monoclonal antibody, and cyclosporine or anti-CD8 antibody (calcineurin inhibitor-free regimen) ^[29]. Accordingly, transient chimerism did not induce tolerance of islet graft survival, with islet function having been lost soon after the disappearance of chimerism ^[29]. Similar to islet transplantation, the induction of transient chimerism did not promote the tolerance of a heart allograft ^[30].

Table 1 summarizes the available evidence regarding the effectiveness of ADL in inducing immunological tolerance in islet transplantation. Studies using rodent islet transplantation models have demonstrated the efficacy of the peritransplant infusion of ECDI-fixed donor splenocytes in not only allogeneic islet transplantation ^[15]^[31] but also xenogeneic islet transplantation ^[32]^[33]. Focusing on evidence that promotes clinical implementation, recent data regarding the NHP model reported by Singh et al. can be considered a breakthrough achievement ^[15]. Their protocol involves peritransplant infusions of MHC-DRB allele-matched apoptotic donor leukocytes under short-term immune suppressions, including antagonistic anti-CD40 antibody 2C10R4, rapamycin, soluble tumor necrosis factor receptor, and anti-interleukin 6 receptor antibody.

Table 1. Summary of previous studies on tolerance induction using ECDI-donor splenocytes in islet transplantation animal experiments.

Summary of Previous Studies on Tolerance Induction Using ECDI-Donor Splenocytes in Islet Transplantation Animal Experiments
Year	Authors	Tx Model	Induction Treatments	Tx Outcome	Mechanisms
2008	Luo et al.	mouse-to-mouse (allogeneicTx model)	ECDI-SPs	64% graft survival (>100 days)	Depletion of alloantigen-specific T cells CD4+CD25+ Tregs are required for tolerance induction by infusion of ECDI-treated donor splenocytes. PD-1/PD-L1 signaling pathway is associated with donor-specific tolerance induction by ECDI-fixed SPs
2013	Wang et al.	rat-to-mouse (xenogeneic Tx model)	ECDI-SPs	MST 48 days (18days for non-treated)	Anti-donor antibody: rat ECDI-SPs induced anti-rat IgGs (High levels of anti-rat IgG were detectable by day 14) C4d deposition: observed 14 days and 28 days in rat islet xenograft from recipients treated with rat ECDI-SPs. B cell activation: upregulated expression of costimulatory molecules CD80, CD86, CD40, and OX40L B cell infiltration: observed in ECDI-SPs recipients 2 or 4 weeks after Tx.
2013	Wang et al.	rat-to-mouse (xenogeneic Tx model)	ECDI-SPs with B cell depletion	100% graft survival (>100 days)	Anti-donor antibody: no production of anti-rat antibodies of all IgG subclasses at 14 days after ECDI-SPs C4d deposition: negative B cell activation: N.A B cell infiltration: minimal infiltration of B220 cells xeno-specific T-cell priming: suppressed memory T cell generation: suppressed rebound B cells: xeno-donor-specific B cell unresponsiveness
2017	Kang et al.	pig-to-mouse (xenogeneic Tx model)	no treatment	acute rejection (by day 7–26 post-transplantation)	B cell infiltration to grafts; prominent (cf. minimal infiltration of B cells to graft in alloislet Tx) High expression of IL-17 on CD4 and CD8T cell from rejected mice (cf. high levels of IFN-r on T cell from rejected mice in alloislet Tx.)
			ECDI-SPs only	no prolongation of graft survival	N.A
			ECDI-SPs with B cell depletion	prolongation of graft survival(40% graft >100 days)	N.A
			ECDI-SPs with B cell depletion and transient rapamycin	1. prolongation of graft survival(65% graft >100 days) 2. late rejection between day 100 and 200 post-transplantation (B cell reconstitution)	initial phase(day 21–70 post transplantation) anti-pig IL-17 response: suppressed rejection phase B cell infiltration to graft: aggressive infiltration of B cells to graft anti-pig antibody production: minimal anti-pig INFr response; observed in indirect donor stimulation, but not direct donor stimulation
2019	A.Sigh	HNP-to-NHP (MHC lassⅡ matched) (allogeneic Tx model)	ECDI-SPs and transient ISs (anti-CD40, anti-IL-6R, anti-TNFaR, rapamycin)	long-term tolerance (100%)	antigen-specific regulatory networks: Tr1, Breg, B10, MDSC One DRB-matched ECDI-SPs; expanded alloantigen-specific regulation
2020	Dangi et al.	mouse(B6)-to-mouse(Balb/c) (allogeneic islet transplantation)	ECDI-SPs only	no prolongation of graft survival
			ECDI-SPs and transient ISs (anti-CD40 and rapamycin)	MST 35 days	donor-specific graft-infiltrating T cells; inhibited expansion of donor-specific memory B cells; inhibited infiltrating B cells in late rejected islets with high expression of CD40 and CD86
			ECDI-SPs and transient ISs (anti-CD40 and rapamycin)B cell depletion	islet survival of >180 days in ~80% of recipients

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