A Significant Role for Histocompatibility in Human Islet Transplantation

Mohanakumar, T.; Narayanan, Kishore; Desai, Niraj M.; Ramachandran, S.; Shenoy, Surendra; Jendrisak, Martin D.; Süßkind, B.; Olack, Barbara; Benshoff, N.; Phelan, D.; Brennan, Daniel C.; Fernández, Luis A.; Odorico, Jon S.; Polonsky, Kenneth S.

doi:10.1097/01.tp.0000226161.82581.b2

Cited by 63 publications

(61 citation statements)

References 24 publications

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“…hESC re-injection induced a boost in HLA I IgG antibodies, as has been reported after MSC transplantation in swine (Cho et al, 2008). Even non-cytotoxic alloantibodies detected by flow cross-match, which are negative in conventional complement-dependent lymphocytotoxic cross-match, have been reported to be sufficient to cause immunologic damage of transplanted islets (Mohanakumar et al, 2006). The antibody surge in our study occurred rapidly (within 5 days) and accompanied the strong cellular immune activation.…”

Section: Discussionsupporting

confidence: 55%

“…The importance of antibody-mediated rejection after cell transplantation is gaining increasing awareness and has already been reported for hematopoietic (Spellman et al, 2010) and mesenchymal stem cell (MSC) transplantation (Beggs et al, 2006;Cho et al, 2008) and for islet transplantation (Mohanakumar et al, 2006). FACS-based DSA quantification using living cells identifies all bound antibodies both against HLA and non-HLA epitopes.…”

Section: Discussionmentioning

confidence: 99%

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Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

Deuse¹,

Seifert²,

Tsao³

et al. 2011

Journal of Cell Science

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KD was followed by flow cytometry and showed levels between 1% and 12% of those of naïve hESC between days 7 and 42 (means ± s.e.m.). (b) A total of 10 6 hESCs or hESC KD were transplanted into the gastrocnemius muscle of either immunocompetent Balb/c or severely immunocompromised SCID-beige mice. All ten Balb/c mice rapidly rejected the hESC transplants, whereas the cells survived in ten SCID-beige recipients. Rejection of hESC KD was markedly attenuated and four out of ten hESC KD grafts achieved long-term survival. 4128 Author Correction The first author apologises for these errors.Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells SummaryHuman embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESC KD ). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESC KD was 88%-99% reduced. T cell activation after hESC KD transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESC KD was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESC KD was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

Deuse¹,

Seifert²,

Tsao³

et al. 2011

Journal of Cell Science

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“…Studies from our lab and others have shown that preexisting or de novo production of anti-HLA Abs result in poor islet allograft function (20,26 Figure 6A.…”

Section: Sensitization To Donor Mhc Molecules Increases the Levels Ofmentioning

confidence: 99%

“…Islets from murine pancreata were isolated and transplanted as described in our earlier publicaions (18,19 (20,21 (22). …”

Section: Mouse Islet Isolation Transplant and Immunosuppressionmentioning

confidence: 99%

Activated Effector and Memory T Cells Contribute to Circulating sCD30: Potential Marker for Islet Allograft Rejection

Saini

Ramachandran

Angaswamy

et al. 2008

American Journal of Transplantation

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T-cell activation up-regulates CD30 resulting in an increase in serum soluble CD30 (sCD30). CD4+ T cells, a major source for sCD30, play a significant role in the pathogenesis of rejection. In this study, sCD30 was measured pre-and posttransplant in mouse islet allograft models and human islet allograft recipients. sCD30 was measured by ELISA in diabetic C57BL/6, CD4Knockout (KO) and CD8KO islet allograft recipients. sCD30 increased significantly prior to rejection (1.8 ± 1 days) in 80% of allograft recipients. Sensitization with donor splenocytes, or a second graft, further increased sCD30 (282.5 ± 53.5 for the rejecting first graft vs. 374.6 ± 129 for the rejecting second graft) prior to rejection suggesting memory CD4+ T cells contribute to sCD30. CD4KO failed to reject islet allograft and did not demonstrate sCD30 increase. CD8KO showed elevated (227 ± 107) sCD30 (1 day) prior to rejection. High pretransplant sCD30 (>20 U/ml) correlated with poor outcome in human islet allograft recipients. Further, increase in sCD30 posttransplant preceded (3-4 months) loss of islet function. We conclude that sCD30 is released from activated CD4 T cells prior to islet allograft rejection and monitoring sCD30 can be a valuable adjunct in the follow-up of islet transplant recipients.

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“…Notably, IAK graft loss occurred without jeopardizing the function of the transplanted kidney (15,19). A positive association between allosensitization and islet graft loss (dysfunction or rejection) has been described in only few sequential ITA recipients (17,20,21), particularly in presensitized recipients (21). (Table 1).…”

mentioning

confidence: 99%

Allosensitization of Islet Allograft Recipients

et al. 2007

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A Significant Role for Histocompatibility in Human Islet Transplantation

Abstract: Patient selection based on sensitization to donor HLA may be one of the factors crucial for the success of islet transplant. Further, in some patients, rejection of islets can be associated with sensitization to mismatched donor histocompatibility antigens.

Cited by 63 publications

References 24 publications

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

Activated Effector and Memory T Cells Contribute to Circulating sCD30: Potential Marker for Islet Allograft Rejection

Allosensitization of Islet Allograft Recipients

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