MHC-Mismatched Islet Allografts Are Vulnerable to Autoimmune Recognition In Vivo

Hematopoietic chimerism is considered to generate robust allogeneic tolerance; however, tissue rejection by chimeras can occur. This “split tolerance” can result from immunity toward tissue-specific Ags not expressed by hematopoietic cells. Known to occur in chimeric recipients of skin grafts, it has not often been reported for other donor tissues. Because chimerism is viewed as a potential approach to induce islet transplantation tolerance, we generated mixed bone marrow chimerism in the tolerance-resistant NOD mouse and tested for split tolerance. An unusual multilevel split tolerance developed in NOD chimeras, but not chimeric B6 controls. NOD chimeras demonstrated persistent T cell chimerism but rejected other donor hematopoietic cells, including B cells. NOD chimeras also showed partial donor alloreactivity. Furthermore, NOD chimeras were split tolerant to donor skin transplants and even donor islet transplants, unlike control B6 chimeras. Surprisingly, islet rejection was not a result of autoimmunity, since NOD chimeras did not reject syngeneic islets. Split tolerance was linked to non-MHC genes of the NOD genetic background and was manifested recessively in F1 studies. Also, NOD chimeras but not B6 chimeras could generate serum alloantibodies, although at greatly reduced levels compared with nonchimeric controls. Surprisingly, the alloantibody response was sufficiently cross-reactive that chimerism-induced humoral tolerance extended to third-party cells. These data identify split tolerance, generated by a tolerance-resistant genetic background, as an important new limitation to the chimerism approach. In contrast, the possibility of humoral tolerance to multiple donors is potentially beneficial.

Section: Discussionmentioning

confidence: 99%

“…In this regard, the indirect pathway of rejection by CD4 T cells is unusually potent in NOD mice (33,34). Hence, we have recently investigated the issue of differential tissue sensitivity to CD4-mediated indirect rejection in a TCR-transgenic model.…”

Section: Discussionmentioning

confidence: 99%

Development of Either Split Tolerance or Robust Tolerance along with Humoral Tolerance to Donor and Third-Party Alloantigens in Nonmyeloablative Mixed Chimeras

Chan¹,

Razavy

Luo

et al. 2008

“…Importantly, CD4 T cells with known antigenic specificities have been shown to reject transplants following direct (7,17,18) or indirect (7,17) activation, in the absence of immunity from CD8 T or B cells, and in the absence of any demonstrable antigenic crossreactivity (7). Moreover, indirect CD4 responses may be particularly important in xenograft rejection (19), and alloimmunity and/or autoimmunity generated by NOD mice toward islet transplants (6,20,21). In contrast, tolerance induction in certain transplant situations may depend on the indirect pathway (22).…”

Section: D4 T Cells Frequently Help To Activate Cd8 T and B Cells Tmentioning

confidence: 99%

Differential Susceptibility of Allogeneic Targets to Indirect CD4 Immunity Generates Split Tolerance

Chan

Razavy

Anderson

2008

CD4 T cells frequently help to activate CD8 T and B cells that effect transplant rejection. However, CD4 T cells alone can reject transplants, either directly or indirectly. The relative effectiveness of indirect CD4 immunity in rejecting different types of allogeneic grafts is unknown. To address this, we used a TCR transgenic mouse model in which indirect CD4 alloimmunity alone can be studied. We challenged transgenic recipients with hematopoietic cells and shortly thereafter skin transplants that could only be rejected indirectly, and observed Ag-specific indirect donor B cell and skin rejection, but not T cell elimination, reflecting a state of split tolerance. Deficiency of indirect CD4 alloimmunity in donor T cell rejection was also apparent when acute indirect rejection of donor islets occurred despite generation and maintenance of mixed T cell chimerism, due to migration of the few passenger T cells into recipient circulation. Although passenger lymphocytes delayed indirect islet rejection, they enhanced rejection by a full repertoire capable of both direct and indirect reactivity. Interestingly, the persistence of chimerism was associated with the eventual development of tolerance, as demonstrated by acceptance of donor skin grafts given late to hematopoietic cell recipients, and hyporesponsiveness of transgenic T cells from islet recipients in vitro. Mechanistically, tolerance was recessive and associated with progressive down-regulation of CD4. Collectively, our data indicate that indirect CD4 immunity is not equally destructive toward different types of allogeneic grafts, the deficiency of which generates split tolerance. The futility of these responses can convert immunity into tolerance.

“…However, it is still unknown whether this approach can be applied to autoimmune patients such as patients with type 1 diabetes (T1D) who need islet and/or kidney transplantation. Allografts can be rejected by both alloimmunity and autoimmunity in autoimmune recipients (9)(10)(11)(12), pathogenic autoreactive T cells can be cross-reactive with alloantigens (13), and pathogenic autoreactive T cells in NOD mice and T1D patients possess promiscuous TCRs that have cross-reactivity (14)(15)(16)(17)(18); but it remains unclear whether the T cells that mediate alloimmunity and autoimmunity can be the same T cells.…”

mentioning

confidence: 99%

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

Wang

Racine

Zhang

et al. 2014

In nonautoimmune recipients, induction of mixed and complete chimerism with hematopoietic progenitor cells from MHC (HLA)-matched or -mismatched donors are effective approaches for induction of organ transplantation immune tolerance in both animal models and patients. But it is still unclear whether this is the case in autoimmune recipients. With the autoimmune diabetic NOD mouse model, we report that, although mixed and complete MHC-mismatched chimerism provide immune tolerance to donor-type islet and skin transplants, neither mixed nor complete MHC-matched chimerism does. The MHC-mismatched chimerism not only tolerizes the de novo developed, but also the residual pre-existing host-type T cells in a mismatched MHC class II–dependent manner. In the MHC-mismatched chimeras, the residual host-type peripheral T cells appear to be anergic with upregulation of PD-1 and downregulation of IL-7Rα. Conversely, in the MHC-matched chimeras, the residual host-type peripheral T cells manifest both alloreactivity and autoreactivity; they not only mediate insulitis and sialitis in the recipient, but also reject allogeneic donor-type islet and skin grafts. Interestingly, transgenic autoreactive BDC2.5 T cells from Rag1+/+, but not from Rag1−/−, NOD mice show alloreactivity and mediate both insulitis and rejection of allografts. Taken together, MHC-mismatched, but not MHC-matched, chimerism can effectively provide transplantation immune tolerance in autoimmune recipients.