Antibody-mediated targeting of CD45 isoforms: A novel immunotherapeutic strategy

Basadonna, Giacomo; Auersvald, Luiz Augusto; Khuong, Chau Q.; Zheng, Xin Xiao; Kashio, Nobuyuki; Zekzer, Dan; Minozzo, M.; Qian, Heying; Visser, Lydia; Diepstra, Arjan; Lazarovits, Andrew I.; Poppema, Sibrand; Strom, Terry B.; Rothstein, David M.

doi:10.1073/pnas.95.7.3821

Cited by 89 publications

(96 citation statements)

References 45 publications

(58 reference statements)

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“…Anti-CD25 (PC61) was purified from hybridoma supernatants using protein G according to the manufacturer's recommendation (Pharmacia). CD45RB expression was analyzed by staining with directly conjugated anti-CD45RB (clone 16A), which does not cross-react with the epitope bound by MB23G2 (16,19). Intracellular CTLA-4 expression was determined by permeabilization with 0.5% saponin after fixation (2% paraformaldehyde) followed by incubation with directly conjugated anti-CTLA-4 or control hamster Ig, as we described (19).…”

Section: Abs and Immunofluorescencementioning

confidence: 99%

“…; Sigma-Aldrich) and confirmed by persistent hyperglycemia (blood glucose Ͼ350 mg/dl on 2 days) (16). After in situ digestion with collagenase V (Sigma-Aldrich; 1 mg/ml), islets were purified by filtration through a 100-um nylon cell strainer (BD Biosciences) and then hand-picked under a stereomicroscope, as we described (21).…”

Section: Islet Isolation and Transplantationmentioning

confidence: 99%

“…After in situ digestion with collagenase V (Sigma-Aldrich; 1 mg/ml), islets were purified by filtration through a 100-um nylon cell strainer (BD Biosciences) and then hand-picked under a stereomicroscope, as we described (21). Four hundred islets were transplanted under the left kidney capsule of C57BL/6 recipients (16,19). Blood glucose of Ͻ200 mg/dl within 2 days after transplantation and Ͼ250 mg/dl (after initial engraftment) defined primary graft function and graft loss, respectively.…”

Section: Islet Isolation and Transplantationmentioning

confidence: 99%

“…Peripheral conversion from this "naive" phenotype toward expression of the lower (CD45RB low ) M r CD45 isoforms normally occurs with T cell activation and is purported to be unidirectional (24,26,27). Although in the setting of anti-CD45RB treatment, conversion from CD45RB high to CD45RB low expression occurs in the absence of CD4 cell activation (16,19). Regardless, reappearance of CTLA-4 Ϫ CD45RB high CD4 cells starting 7-10 days after anti-CD45RB treatment can only occur through emergence of naive CTLA-4 Ϫ CD45RB high CD4 cells from the thymus, or through previously unrecognized phenotypic reversion in the periphery.…”

Section: Thymectomy Prolongs Increased Ctla-4 Expressionmentioning

confidence: 99%

“…We have shown that as a single agent, anti-CD45RB induces long-term islet allograft survival in 50% of recipients across immunogenic murine strain combinations (16). Anti-CD45RB also promotes tolerance in murine cardiac and renal transplantation (17,18).…”

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confidence: 98%

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Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Salvalaggio¹,

Camirand

Ariyan³

et al. 2006

The Journal of Immunology

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The role of CTLA-4 in tolerance is primarily inferred from knockout and blocking studies. Anti-CD45RB mediates allograft tolerance in mice by inducing CTLA-4 expression on CD4 cells, providing a novel opportunity to determine how therapeutic enhancement of CTLA-4 promotes tolerance. We now show that induced CTLA-4 expression normally resolves by day 17. Although thymectomy prolongs enhanced CTLA-4 expression, long-term engraftment is unaffected. To address the temporal relationship between increased CTLA-4 expression and engraftment, transplantation was delayed for various times after anti-CD45RB treatment. Delaying transplantation for 7 days (when CTLA-4 expression had peaked but treatment mAb was no longer detectable), resulted in long-term engraftment comparable to transplantation with no delay (day 0). Delaying transplantation from 10 to 18 days led to a progressively poorer outcome as CTLA-4 expression returned to baseline. This suggested that Ag exposure while CTLA-4 expression is enhanced is sufficient to induce long-term engraftment. To substantiate this, on day 0, anti-CD45RB-treated mice received BALB/c vs unrelated alloantigen, followed by transplantation of BALB/c islets 10 days later. Whereas recipients exposed to unrelated Ag experienced acute rejection, recipients exposed to donor Ag achieved long-term engraftment. Anti-CD45RB-treated mice exposed to alloantigen exhibited anergic CD4+CD25− effector cells and regulatory CD4+CD25+ cells. Moreover, CD25 depletion in the peritransplant period prevented anti-CD45RB-mediated engraftment. Thus, exposure of CD4 cells expressing CTLA-4 to donor Ag is necessary and sufficient to induce long-term engraftment which appears to be mediated by both regulation and anergy.

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Section: Abs and Immunofluorescencementioning

confidence: 99%

Section: Islet Isolation and Transplantationmentioning

confidence: 99%

Section: Islet Isolation and Transplantationmentioning

confidence: 99%

Section: Thymectomy Prolongs Increased Ctla-4 Expressionmentioning

confidence: 99%

mentioning

confidence: 98%

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Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Salvalaggio¹,

Camirand

Ariyan³

et al. 2006

The Journal of Immunology

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Islet transplantation: present and future perspectives

Kenyon

Ranuncoli

Masetti

et al. 1998

Diabetes Metab. Rev.

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Islet cell transplantation can potentially normalize blood glucose levels and stop the progression of clinical complications, and if the transplant is done early in the course of the disease complications may be prevented. Remarkable progress has been made in recent years and islet cell transplantation has resulted in normalization of metabolic control in several patients with Type 1 diabetes in the absence of hypoglycemia. Only a few patients, however, have achieved insulin independence. Issues relating to islet cell engraftment within the liver, prevention of rejection and recurrent autoimmunity, and identification of alternative immunosuppressive drugs that do not adversely affect islet cell function remain to be solved. Thus far, the need for chronic, generalized immunosuppression to prevent rejection of the islets has limited the indication to those patients who have already received another transplant or to those who simultaneously receive islets and another organ (generally a kidney). Identification of immunointervention protocols that allow for engraftment in the absence of deleterious effects on the islets and prevent rejection and recurrent autoimmunity would make this procedure suitable for all patients, including children who have not yet developed long-term complications of the disease.

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Long‐Term Survival of Allograft Murine Islets Coated via Covalently Stabilized Polymers

Rengifo

Giraldo

Labrada

et al. 2014

Adv Healthcare Materials

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Clinical islet transplantation (CIT) has emerged as a promising treatment option for type 1 diabetes mellitus (T1DM); however, the anti-rejection drug regimen necessary to mitigate allograft islet rejection is undesirable. The use of polymeric coatings to immunocamouflage the transplant from host immune attack has great potential. We have recently developed alginate and poly(ethylene glycol) (PEG)-based polymers, functionalized with azide and phosphine, respectively, which form spontaneous and chemoselective crosslinks via the bioorthogonal Staudinger ligation scheme. Herein, we explored the utility of these polymers to form immunoprotective, ultrathin coatings on murine primary pancreatic islets. Resulting coatings were nontoxic, with unimpaired glucose stimulated insulin secretion. Transplantation of coated BALB/c (H-2 d ) islets into streptozotozin-induced diabetic C57BL/6 (H-2 b ) resulted in prompt achievement of normoglycemia, at a rate comparable to controls. A significant subset of animals receiving coated islets (57%) exhibited long-term (> 100 d) function, with robust islets observed upon explantation. Control islets rejected after 15 d (+/− 9 d). Results illustrate the capacity of chemoselectively functionalized polymers to form coatings on islets, imparting no detrimental effect to the underlying cells, with resulting coatings exhibiting significant protective effects in an allograft murine model.

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Antibody-mediated targeting of CD45 isoforms: A novel immunotherapeutic strategy

Cited by 89 publications

References 45 publications

Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Antigen Exposure during Enhanced CTLA-4 Expression Promotes Allograft Tolerance In Vivo

Islet transplantation: present and future perspectives

Long‐Term Survival of Allograft Murine Islets Coated via Covalently Stabilized Polymers

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