Current Diabetes Reports

, 11:337 | Cite as

Blockade of Leukocyte Function Antigen-1 (LFA-1) in Clinical Islet Transplantation

Clinical Trial Report

Trials: Posselt AM, Bellin MD, Tavakol M, et al.: Islet transplantation in type 1 diabetics using an immunosuppressive protocol based on the anti-LFA-1 antibody efalizumab. Am J Transplant 2010, 10(8):1870–1080.

Turgeon NA, Avila JG, Cano JA, et al.: Experience with a novel efalizumab-based immunosuppressive regimen to facilitate single donor islet cell transplantation. Am J Transplant 2010, 10(9):2082–2091.

Rating: Of significant importance.

Keywords Clinical islet transplantation.Type 1 diabetes.LFA-1.Efalizumab.Graft function

Introduction: Restoration of β-cell function is a desirable goal to attain in patients with insulin-dependent diabetes. In recent years, several clinical trials have shown that transplantation of pancreatic islets can achieve a more physiologic metabolic control than exogenous insulin therapy in C-peptide-negative patients with unstable type 1 diabetes (T1D) [1, 2]. This was demonstrated as a normalization of glycated hemoglobin and tightening of daily glycemic excursions, which parallel restoration of C-peptide with significant reduction of, or complete independence from, exogenous insulin treatment. Importantly, these results were also associated with significant amelioration of quality of life, which paralleled the abrogation of severe hypoglycemic events that represented the main indication for transplant. However, the achievement of insulin independence generally required the use of multiple donor islet preparations in these trials, which represents a remarkable drawback due to the shortage of organs and the costs associated with the isolation of islet cells. Progressive islet graft dysfunction has been described over time [3, 4, 5], which may be the result of a combination of variables, including the engraftment of a marginal β-cell mass exposed to high metabolic demand and to immunosuppressive drug toxicity, among others [6]. Furthermore, immunosuppressive drugs also may impact other organs, and of particular concern is the potential worsening of kidney function in a population of patients at risk to develop end-stage renal disease.

The development of novel clinical protocols based on the use of biologics with more specific targeting of immune cell compartments and lacking organ toxicity as an alternative to standard immunosuppressive drugs is appealing. Emerging clinical data indicate that the use of lymphodepleting induction agents and peritransplant anti-inflammatory treatment positively impact both short- and long-term graft function after islet transplantation [7]. Also, recent immunosuppressive protocols have avoided the use of calcineurin inhibitors (CNIs) or molecular target of rapamycin (mTOR) inhibitors as chronic immunosuppression in islet transplant recipients in an attempt to overcome long-term toxicity and prolong graft function. In this direction, two recent clinical trials have reported the use of anti-leukocyte function antigen-1 (anti-LFA-1) antibody efalizumab (anti-CD11a; Raptiva®; Genentech, South San Francisco, CA) in clinical islet transplantation in patients with T1D [8, 9]. Both trials have shown encouraging results with improved clinical outcomes.

The leukocyte function antigen-1 (LFA-1) [10] is a β2 integrin comprising a noncovalently linked heterodimer between an α (CD11a) and β chain (CD18). The primary ligand of LFA-1 is the intercellular adhesion molecule-1 (ICAM-1) [11]. LFA-1 has been recognized as an adhesion molecule involved in leukocyte trafficking, binding, and transmigration (Fig. 1). LFA-1 plays a key role in cell-to-cell interactions participating to the immunologic synapse to stabilize T-lymphocyte engagement with antigen-presenting cells (APCs) to achieve optimal T-cell activation (Fig. 1a). Expression of LFA-1 has been mainly described on T lymphocytes, particularly memory subsets, and recently it has been suggested that it may also have a role in the antigen presentation function of B-cells. Deficiency of LFA-1 in mice, or the use of anti-LFA-1 antibodies, impairs leukocyte (T-cell and neutrophil) ability to cross endothelial cell monolayers in response to chemotactic gradient stimulation (Fig. 1b). LFA-1 also functions as a costimulatory signaling molecule between T lymphocytes and APCs, and may result in the activation of Th1 immunity, whereas interference with LFA-1:ICAM-1 engagement skews it toward a Th2 response (Fig. 1c).
Fig. 1

Schematic representation of known LFA-1 functions in immunity (left panels) and effect of its blockade (right panels). a, LFA-1 seems involved in the stabilization of T-cell engagement with APC and in the optimal activation of T cells. Upon TCR engagement, LFA-1 is localized in the center of the T-cell-APC contact region, with the TCR being localized at the periphery of the synapse. With synapse maturation, the TCR moves from the periphery to the center of the T-cell-APC contact increasing the number of engaged TCRs, as LFA-1 moves to the periphery. Blockade of LFA-1 may therefore affect the stability of the immunologic synapse. b, LFA-1 seems the key integrin involved in leukocyte arrest and transmigration from vascular endothelium in response to inflammation in a target tissue. Blockade of LFA-1 in vivo may results in reduced pathogenic lymphocyte and neutrophil transmigration in transplanted tissues. c, LFA-1 interaction with its ligand ICAM-1 has been proposed as a costimulatory pathway able to activate signal transduction and regulate transcription factors in T cells. APC antigen-presenting cell; ICAM-1 intercellular adhesion molecule-1; LFA-1 leukocyte function antigen-1; MHC major histocompatibility complex; TCR T-cell receptor

In experimental models of solid organ and cellular transplantation, LFA-1 blockade has shown promise allowing prolongation of allograft survival. Addition of anti-LFA-1 antibody to murine or nonhuman primate mixed lymphocyte reactions results in suppressed lymphocyte proliferation in the presence of alloantigens [12, 13]. In the context of islet transplantation studies, short-term anti-LFA-1 treatment results in long-term acceptance of allogeneic islets when used in murine models of chemically induced diabetes [10, 14, 15, 16, 17]. In a preclinical study, short-term (up to 35 days) anti-LFA-1 antibody therapy (TS-1/22; mouse anti-human CD11a antibody) in combination with anti-interleukin-2 receptor antibody induction and mTOR inhibitor treatment for 80 days resulted in permanent acceptance of allogeneic islet grafts in chemically induced diabetic nonhuman primates, suggesting the ability to induce operational tolerance with this approach [13]. However, alloantibody formation was not prevented by this regimen in animals bearing a functional graft long-term, whereas combination of anti-LFA-1 and costimulation blockade using another biologic agent belatacept (CLTA4Ig) resulted in long-term survival without alloantibody formation in this preclinical animal model [13].

In the context of autoimmune diabetes models, LFA-1 blockade using either anti-LFA-1 or anti-ICAM-1 antibodies alone or in combination effectively prevented both the onset and also transfer of the disease in a murine model of T1D, the nonobese diabetic (NOD) mouse [18, 19, 20]. The impact of a short-term anti-LFA-1 antibody treatment alone in spontaneously diabetic NOD mice was partially efficacious, resulting only in delayed allograft rejection [12]. A synergistic effect was observed when combining extended anti-LFA-1 antibody treatment with costimulation blockade (ie, CTLA4Ig or CD154 antibody), with T-cell depletion or immunosuppression (ie, mTOR inhibitors) in spontaneously diabetic NOD mice receiving allogeneic or xenogeneic islet grafts [12, 21].

Efalizumab (Raptiva®) is a humanized monoclonal antibody that blocks the CD11a subunit of LFA-1 [10, 22]. Clinical phase 1 and 2 trials have shown the efficacy of the use of efalizumab in preventing renal allograft rejection [22]. Also, chronic administration of efalizumab has been used in phase 3 clinical trials to treat psoriasis, in where it showed long-term efficacy and safety [23]. After the report of four cases of progressive multifocal leukoencephalopathy (PML) in patients with psoriasis receiving efalizumab therapy for more than 4 years (on a sample of ~40,000 patients), the manufacturer voluntarily withdrew the drug [24]. Thus, all trials utilizing efalizumab, including the two discussed herein, had to convert study subjects to different immunosuppressive regimens.

Aims: To evaluate the inclusion of LFA-1 blockade using efalizumab as part of immunosuppressive protocols for non-uremic patients with unstable T1D undergoing allogeneic islet transplantation.

Methods: Two recent clinical pilot trials have reported the use of efalizumab in patients with T1D who were recipients of allogeneic islets [8, 9]. The immunosuppressive protocols utilized in these trials are summarized in Table 1. The first trial was carried on at the University of California at San Francisco (UCSF) and included a cohort of eight subjects who received a lymphodepleting induction regimen based on thymoglobulin for the first islet infusion and a course of anti-CD25 (CD25 is the interleukin-2 receptor) antibody (basiliximab) as induction in case of subsequent islet transplants, and maintenance immunosuppression with “de novo” purine synthesis inhibitors (mycophenolic acid), mTOR inhibitor (sirolimus) and efalizumab [8]. The second trial was carried on at Emory University on two experimental groups [9]: eight subjects received a conventional immunosuppressive regimen based on an induction for each islet infusion with anti-CD25 antibody (daclizumab) and maintenance immunosuppression with mTOR inhibitors and a CNI (tacrolimus), as described in the original Edmonton trial [25]. Four subjects received similar anti-CD25 antibody induction protocol, with a maintenance immunosuppression based on CNI (tacrolimus), “de novo” purine synthesis inhibitor (mycophenolate mofetil), and efalizumab [9]. In the latter trial, the primary end point was insulin independence at 75 ± 5 days after the first islet cell infusion; secondary end points included the proportion of subjects achieving insulin independence and normal hemoglobin A1c (HbA1c) one year after single islet infusion [9].
Table 1

Immunosuppressive regimens utilized in the two clinical trials

 

UCSF—Posselt et al. [8]

Emory—Turgeon et al. [9]

Efalizumab protocol

Edmonton protocol

Efalizumab protocol

Study subjects (n)

8

8

4

Induction therapy

1st islet graft

Thymoglobulin 4 mg/kg IV in two doses at day −2 and −1

Anti-CD25 antibody (daclizumab) 1 mg/kg IV on days 0, 14, 28, 32, 46

Anti-CD25 antibody (daclizumab) 1 mg/kg IV on days 0, 14, 28, 32, 46

Subsequent islet graft(s)

Anti-CD25 antibody (basiliximab) 20 mg IV on days 0 and 4

Anti-CD25 antibody (daclizumab) 1 mg/kg IV on days 0, 14, 28, 32, 46

Anti-CD25 antibody (daclizumab) 1 mg/kg IV on days 0, 14, 28, 32, 46

Maintenance immunosuppression

“De novo” purine synthesis inhibitor

Mycophenolic acid 360–720 mg PO bid from day 0

Mycophenolate mofetil 1000 mg bid from day 0

Calcineurin inhibitor

Tacrolimus

Tacrolimus

 

1.0 mg bid starting on day 0

1.0 mg bid starting on day 0

 

Target trough levels:

Target trough levels:

 

8–10 ng/mL during 1st month

8–10 ng/mL during 1st month

 

5–8 ng/mL during 2nd month

5–8 ng/mL during 2nd month

 

3–5 ng/mL by 6th month

3–5 ng/mL by 6th month

  

Discontinue at 6 or 12 months

mTOR inhibitor

Sirolimus

Sirolimus

Target trough levels ≥8 ng/mL

0.2 mg/kg day 0

 
 

0.1 mg/kg qid

 
 

Target trough levels 12–15 ng/mL

 

Anti-LFA-1 antibody (efalizumab)

1.0 mg/kg, weekly starting on day −1

1.0 mg/kg, weekly starting on day 0

0.5 mg/kg, weekly starting on 3 rd month

  

Anti-LFA-1 anti-leukocyte function antigen-1; bid twice a day; IV intravenous; mTOR molecular target of rapamycin; PO oral; qid ones a day; UCSF University of California at San Francisco

Results and Discussion: Both trials showed good islet engraftment in the recipients treated with efalizumab. In particular, insulin independence was achieved with a mean of 30 ± 21 days after transplantation of a single-donor islet preparation in half of the study subjects (n = 4) in the UCSF trial [8] receiving a mean islet mass of 9254 islet equivalents (IEQ) per kilogram of body weight (range: 6291–11,023). All other subjects in this trial achieved insulin independence after the last islet infusion (three subjects received collectively two and one subject three islet preparations) [8]. In the Emory trial [9], the primary end point, following the metrics of the US National Institutes of Health Clinical Islet Transplant Consortium (http://www.citisletstudy.org), was insulin independence at 75 ± 5 days after single islet transplantation. All four study subjects receiving efalizumab achieved the primary end point with a single-donor islet infusion and a mean islet mass of 8119 IEQ/kg (range: 5722–9901). The primary end point was achieved in 2/8 (25%) of the subjects receiving the “Edmonton protocol” (12,269 and 18,768 IEQ/kg, respectively). Four additional subjects achieved insulin independence after transplantation of three (n = 1) or two (n = 3) islet preparations, respectively, whereas two subjects did not achieve insulin independence in this group [9].

Although different treatments were used in these study groups, it is conceivable that LFA-1 blockade exerted a beneficial effect on islet engraftment in the critical early post-transplant period, when islet embolization in the hepatic portal sinusoids reduces functional islet mass engraftment. Increased levels of liver enzymes are invariably reported following intrahepatic islet embolization [26, 27, 28], whereas significantly lower levels of liver enzymes were observed after islet transplantation in the subjects receiving efalizumab, when compared with those who did not in the Emory trial [9].

Glycemic control was improved after transplantation in all subjects, with achievement of HbA1c reduction and significant C-peptide production in both studies. In the Emory trial, the proportion of subjects achieving insulin independence and normal HbA1c one year after single islet infusion (secondary end point of the study) was achieved collectively in 6 of 8 study subjects treated with the “Edmonton protocol” and in all subjects in the “efalizumab protocol” [9]. Long-term graft function (detectable C-peptide) was observed in all subjects in the “Edmonton protocol” with insulin independence at the most recent follow-up in four subjects. All study subjects in the “efalizumab protocol” showed insulin independence at 15 months.

During the course of both trials, efalizumab was voluntarily withdrawn by the manufacturer due to the occurrence of PML in patients treated chronically for psoriasis [1]. Drug withdrawal occurred at different times post-transplant for each study subject and required the implementation of alternative therapy to prevent loss of graft function. Unfortunately, the withdrawal of efalizumab has altered the design of these trials and rendered quite cumbersome reassessing of the effects of the LFA-1 blockade for the treatment of islet transplant recipients in a homogenous sample of study subjects in each trial. In particular, in the UCSF trial patients were converted to a maintenance immunosuppressive regimen based on mycophenolate mofetil and either CNI (tacrolimus) or mTOR inhibitors. The conversion occurred after a mean period of 419 days on efalizumab, with two subjects converted after 126 and 105 days, respectively, both receiving a second islet transplant after this treatment conversion. This change did not appear to affect graft function. In the Emory trial, efalizumab was converted after a mean of 12 ± 10 months (range: 4–26) with a strategy consisting of the introduction of CD28 costimulation blocking antibody abatacept. One subject who achieved sustained insulin independence for 29 months voluntarily withdrew from the study after conversion to abatacept and subsequently resumed insulin therapy. Two subjects with sustained insulin independence experienced graft failure after conversion to abatacept (4 and 3 months later). One subject was converted to abatacept 4 months after islet transplant starting mTOR inhibitors 2.5 months after conversion and remained insulin independent at the 16-month follow-up.

Nephrotoxicity of CNIs and mTOR inhibitors has been recognized as the cause of progressive loss of renal function in organ transplant recipients. Worsening of renal function is particularly concerning in patients with long-standing diabetes who may develop diabetic nephropathy. Progressive renal dysfunction in patients with T1D receiving chronic immunosuppression after islet transplantation has been reported [4, 29], even though careful pretransplant evaluation of islet transplant candidates and medical management of risk factors (ie, using angiotensin-converting enzyme inhibitors and statins) contribute to reducing this phenomenon [30, 31]. Importantly, in both efalizumab trials, preservation of renal function was observed in study subjects. Glomerular filtration rates (GFR), measured as iohexol clearance, remained stable and urinary protein and albumin excretion in 24-hour urine collections were stable or improved in all patients in the UCSF trial [8]. Similarly, no clinically significant changes in serum creatinine and GFR (measured using the Modification of Diet in Renal Disease calculation) were reported in the Emory trial [9].

No adverse events (AEs) were associated with the use of efalizumab in both trials, besides the development of a self-limited, transient rush at the injection site [8]. In the Emory trial, a significant lower incidence of AEs was recorded in the patients receiving the efalizumab protocol when compared with the “Edmonton protocol” (16 total AEs with a ratio of 4 per subject vs 80 total AEs with a ratio of 10 per subject) [9]. Also, three of the subjects in the “efalizumab protocol” group displayed detectable Epstein-Barr virus (EBV) titers after transplantation without developing EBV symptoms or post-transplant lymphoproliferative disorder. Dose reduction of efalizumab and mycophenolate mofetil resulted in EBV titer reductions in these subjects [9].

Regarding the immunologic impact of LFA-1 blockade, study subjects in the UCSF trial were studied over time and displayed increased proportions of circulating CD4+FoxP3+ T cells also expressing additional markers (eg, CD25hi and CD127lo) specific for a T-regulatory (Treg) cell phenotype in peripheral blood after transplantation. In addition, evaluation of effector T-cells (Teff) based on the production of interferon-γ showed a reduction in this cell population and showed hyporesponsiveness specifically toward donor cell stimulation in most patients tested, whereas third-party responses were preserved [8]. One subject who displayed sustained response to donor antigens in vitro experienced graft dysfunction indicating loss of islet mass possibly due to immune rejection [8]. In the Emory trial, half of the study subjects receiving the “Edmonton protocol” developed donor-specific antibodies, whereas none of the patients in the “efalizumab protocol” did so during the follow-up [9].

Comments

Both clinical studies have the limitation of pilot size clinical trials with small sample size and lack of randomization. Nonetheless, the results of both trials are of high value as they contribute to the assessment of the potential role of biologics as an integral component of the immune therapy armamentarium for islet transplant recipients. Blockade of LFA-1 may offer some peculiar effects on early engraftment (ie, reducing ischemia/reperfusion-like phenomena) that in turn may contribute to enhancing long-term function of transplanted islets. In addition, the putative effects of LFA-1 blockade on T-cell activation and trafficking might contribute to improving long-term outcomes after transplantation [10].

The use of anti-LFA-1 antibodies was associated with high rates of insulin independence with a single donor islet preparation. This effect was evident in the Emory trial, which included an induction protocol based on anti-CD25 antibody treatment combined with immunosuppression, whereas the use of lymphodepletion with thymoglobulin in the UCSF trial may have further contributed to improve early engraftment, as shown in a previous report [32]. Another positive data of both trials was the stable renal function observed using LFA-1 blockade. Given the withdrawal of efalizumab from clinical use during the course of the studies, it is difficult to conclude on the long-term impact of the treatment on graft outcomes. The immunosuppression therapy conversion strategy implemented after withdrawal of efalizumab at UCSF appeared more effective in preserving graft function than the one utilized in the Emory trial. However, the pilot nature of both trials and the remarkable differences in study design make it difficult to point out specific factors associated with better outcome.

An interesting observation in the immunologic studies was the development of hyporesponsiveness toward donor cells while maintaining normal reactivity toward third-party antigens in patients treated with efalizumab. This could suggest that the inclusion of LFA-1 blockade could favor immunoregulatory circuits to donor tissues that could enhance transplant outcome and, if properly harnessed in the context of optimized immunomodulatory protocols, favor the induction of donor-specific tolerance in the absence of chronic immunosuppression in the future [13]. Weaning of immunosuppression without compromising graft function has been possible in experimental animal models of allogeneic islet transplantation after the use of short-course anti-LFA-1 treatment. However, lack of reliable immune monitoring tools that are able to guide the decision to discontinue anti-rejection treatment currently preclude attempting such an approach in the clinical settings.

On a daily basis physicians face the basic rule of primum non nocere (first, do no harm) when weighting risks and benefits for each patient to take appropriate measures to reduce the former without compromising the latter. The use of immunosuppressive and immunomodulatory agents is not free of risks and untoward side effects, including the increased incidence of infections, reactivation and de novo viral infections, cancer (ie, lymphoproliferative disorders), as well as organ toxicity. The use of novel antiviral therapy and changes in the immunosuppressive treatment may help when dealing with viral infections; recently being more timely thanks to the possibility of monitoring viral titers in blood samples. Other conditions, such as PML, are more dreadful, and known to be a risk in severely immune depressed subjects using several of the drugs currently available as anti-inflammatory and anti-rejection options. Importantly, PML has been reported in a small number of subjects receiving efalizumab treatment for more than 4 years. The benefits observed in transplant recipients, including those in the two trials discussed herein, and even following conversion to conventional maintenance immunosuppression in the UCSF trial, showed sustained beneficial effects of a short course of efalizumab on patient outcome and graft function.

In light of the encouraging results in preclinical experimental models in which short-course treatment based on LFA-1 blockade resulted in long-term graft function after discontinuation of immunosuppression [13], it would be desirable to continue clinical testing in well-controlled research settings to further explore the potential of anti-LFA-1 antibody as part of immune therapies. Other biologic agents already in use or currently under testing may have different mechanisms of action (ie, anti-inflammatory effects of antibodies directed to specific cytokines and/or their receptors; antibodies directed to the blockade of costimulatory signaling, among others), and it is conceivable that by developing combinatorial strategies great synergy may result toward achieving much improved clinical outcomes and may be even immune tolerance in interventions trials for autoimmune diseases and organ transplantation in the near future.

Notes

Acknowledgement

A. Pileggi has received grant support from the following agencies: the National Institutes of Health (5R01DK25802, 5R01DK56953, 1U01DK70460, 1R21DK076098, 5R01DK059993, 1DP2DK083096, U01DK089538, 5U42RR016603-08S1, 5U42RR016603, MO1RR16587, 1R01EB008009, and 5U19AI050864-10), the Juvenile Diabetes Research Foundation International (4-2000-946, 4-2000-947, 4-2004-361, 6-39017G1, 4-2008-811 and 17-2010-5), the State of Florida, the University of Miami Interdisciplinary Research Development Initiative, and the Diabetes Research Institute Foundation (www.DiabetesResearch.org). A contract for support of this research, sponsored by United States Congressman Bill Young and funded by a special congressional out of the US Navy Bureau of Medicine and Surgery, is presently managed by the Naval Health Research Center, San Diego, CA. The authors alone are responsible for reporting and interpreting these data; the views expressed herein are those of the authors and not necessarily those of the United States government.

Disclosure

Conflicts of interest: C. Fotino: has performed studies partially supported by Medestea Research; A. Pileggi: is a scientific advisory board member of Converge Biotech, and he has received corporate grant support from Pfizer, Positive ID, and Extended Drug Delivery.

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Diabetes Research Institute, University of MiamiMiamiUSA
  2. 2.DeWitt-Daughtry Department of SurgeryUniversity of Miami Miller School of MedicineMiamiUSA
  3. 3.Department of Microbiology and ImmunologyUniversity of Miami Miller School of MedicineMiamiUSA
  4. 4.Department of Biomedical EngineeringUniversity of MiamiMiamiUSA

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