Campath-1H Induction Plus Rapamycin Monotherapy for Renal Transplantation: Results of a Pilot Study

Knechtle, Stuart J.; Pirsch, John D.; Fechner, John H.; Becker, Bryan N.; Friedl, Andreas; Colvin, Robert B.; Lebeck, Lauralynn K.; Chin, Lisa M.K.; Becker, Yolanda T.; Odorico, Jon S.; D’Alessandro, Anthony M.; Kalayoğlu, Münci; Hamawy, Majed M.; Hu, Huaizhong; Bloom, Debra D.; Sollinger, Hans W.

doi:10.1034/j.1600-6143.2003.00120.x

Cited by 369 publications

(280 citation statements)

References 15 publications

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“…Those data and the present study have important implications in clinical settings. Lymphodepletion is increasingly used as part of newer strategies in solid organ transplantation 5,6 . The occurrence of homeostatic proliferation during lymphoid reconstitution, an event that may be especially relevant in the setting of age-related thymic involution 28 or protocols that employ thymic irradiation, may present a barrier to the establishment of transplantation tolerance, and may also be relevant to selftolerance and autoimmunity.…”

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confidence: 99%

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Homeostatic proliferation is a barrier to transplantation tolerance

Bensinger

Zhang

et al. 2003

Nat Med

385

362

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Despite the ease of inhibiting immune responses by blockade of T-cell costimulation in naive rodent models, it is difficult to suppress those responses in animals with memory cells 1,2 . Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials [3][4][5][6] . But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia. This process, termed homeostatic proliferation 7,8 , may induce acquisition of functional memory T cells 9-13 . Here, using clinically relevant mouse models of peripheral T-cell depletion, we show that residual nondepleted T cells undergo substantial homeostatic expansion. In this setting, costimulatory blockade neither significantly suppresses homeostatic proliferation nor prevents allograft rejection. In addition, T cells that have completed homeostatic proliferation show dominant resistance to tolerance when adoptively transferred into wild-type recipients, consistent with known properties of memory cells in vivo. These findings establish the importance of homeostatic proliferation in clinically relevant settings, demonstrate the barrier that homeostatic proliferation can present to the induction of transplantation tolerance, and have important implications for transplantation protocols that use partial or complete peripheral T-cell depletion.T cells undergo homeostatic proliferation when transferred into severe combined immunodeficiency (scid), recombination-activating gene-deficient or irradiated recipients7 ,8 . In many clinical transplantation protocols, T-cell depletion is less profound. We therefore asked whether residual nondepleted cells could undergo homeostatic proliferation. We treated mice with two doses (100 μg/dose) of depleting monoclonal antibodies directed at CD4 and CD8 (days 0 and 5). This induced 80-90% T-cell depletion, which was maintained for >10 d after the last dose (data not shown).

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mentioning

confidence: 99%

“…Studies demonstrating the importance of alloreactive T-cell deletion during tolerance induction have promoted use of peritransplant T-cell-depleting therapies in clinical trials [3][4][5][6] . But potentially complicating wide-scale, nonspecific T-cell depletion is the finding that extensive T-cell proliferation can occur under conditions of lymphopenia.…”

mentioning

confidence: 99%

Homeostatic proliferation is a barrier to transplantation tolerance

Bensinger

Zhang

et al. 2003

Nat Med

385

362

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“…27 Prospective studies have also compared the use of induction therapies with thymoglobulin or alemtuzumab in renal transplant recipients receiving TAC, TAC and MMF, or SRL. 20,21,28 Acute rejection incidences were 18%, 23%, and 28%, respectively. Despite the high proportion of organs from extended-criteria donors and acute rejection incidence, patients receiving alemtuzumab achieved renal function on average 8.9 mL/min higher than that observed in patients receiving thymoglobulin (61.6 vs. 52.7 mL/ min).…”

Section: Discussionmentioning

confidence: 99%

“…10 Thymoglobulin (Thymoglobuline ® ) is a immunosuppressive agent composed of polyclonal antibodies directed against a When combined with sirolimus (SRL), the incidence of acute rejection episodes was 27.6%, and some of those episodes had a humoral component, requiring specific treatment. 20 The use of alemtuzumab and maintenance of immunosuppression with calcineurin inhibitors and mycophenolate mofetil (MMF), with no corticosteroid, has resulted in reducing the incidence of acute rejection to 9.1%. 21 This was probably due to the fact that memory T cells, more resistant to depletion and to the action of corticosteroids and SRL, are sensitive to calcineurin inhibitors, particularly tacrolimus (TAC).…”

Section: Introductionmentioning

confidence: 99%

Terapia de indução com alentuzumabe em receptores de transplante renal

Sampaio¹,

Freitas²,

Galante³

et al. 2010

J. Bras. Nefrol.

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Introduction: Induction therapy has been used in sensitized patients, re-transplants, and in patients who have high risk to delayed graft function (DGF) after renal transplantation. Methods: Retrospective study with aim to compare transplant endpoints between recipients of deceased donors which have received induction with alemtuzumab (n = 9) versus thymoglobulin (n = 18). Patients were matched for age, duration of dialysis treatment and cold ischemia time. Results: There were no differences at demographic characteristics. All patients received kidney grafts from deceased donors and 67% of these donors met the expanded criteria. The incidence of DFG was similar in alemtuzumab and thymoglobulin groups, 55% and 56%. At 12 months, rates of rejection free survival (67% versus 89%, p = 0,13), graft survival (62,5% versus 76,6%; p = 0,73), graft with death censored (62,5% versus 76,6%; p = 0,82) and patient survival (83,3% versus 81,2%; p = 0,63) were similar between the two groups. Viral infections and renal function were similar between groups. At the end of the first month, alemtuzumab patients displayed a fewer lymphocyte number (135 ± 78 versus 263 ± 112 N/mm 3 , p < 0,05) followed by a more rapid recovery after 3 months (day 90: 683 ± 367 versus 282 ± 72 N/mm 3 ; p < 0,05). Cost associated with alemtuzumab and thymoglobulin inductions therapies were R$ 1,388.00 and R$ 7,398.00. Conclusion: In this cohort of patients, alemtuzumab induction showed efficacy and safety comparable to thymoglobulin but with significant cost reduction.

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“…The use of alemtuzumab has changed the spectrum of infections in transplant patients, and it does not render patients more susceptible to viral or bacterial infections compared to conventional triple immunosuppression. 13 Infections still remain a significant cause of morbidity. 14,15 Recently, our results revealed the alteration of tight junctions and the disruption of intestinal barrier function in intestinal transplantation with the use of alemtuzumab.…”

Section: Introductionmentioning

confidence: 99%

The response of intestinal stem cells and epithelium after alemtuzumab administration

Zhang

Wang

et al. 2011

Cell Mol Immunol

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Intestinal stem cells may have important roles in the maintenance of epithelial integrity during tissue repair. Alemtuzumab is a humanized anti-CD52 lymphocytic antibody that is increasingly being used to induce immunosuppression; intestinal barrier function is impaired during treatment with alemtuzumab. We investigated the response of intestinal stem cells to epithelial damage resulting from alemtuzumab treatment. Intestinal epithelial cell loss and abnormal Paneth cell morphology were found following a single dose of alemtuzumab. The animals receiving alemtuzumab exhibited increased apoptosis in the villi 3 days after alemtuzumab treatment and in the crypt on day 9, but apoptosis was scarce on day 35. We assessed expression of Musashi-1-and Lgr5-positive stem cells following alemtuzumab treatment. Increased numbers of cells staining positive for both Musashi-1 and Lgr5 were found in the stem cell zone after alemtuzumab treatment for 3 and 9 days. These data indicated that the epithelial cells were injured following alemtuzumab treatment, with the associated expansion of intestinal stem cells. After alemtuzumab treatment for 35 days, the numbers of intestinal epithelial cells and intestinal stem cells returned to normal. This study suggests that alemtuzumab treatment induced the increase in stem cells, resulting in the availability of more enterocytes for repair.

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Campath-1H Induction Plus Rapamycin Monotherapy for Renal Transplantation: Results of a Pilot Study

Cited by 369 publications

References 15 publications

Homeostatic proliferation is a barrier to transplantation tolerance

Homeostatic proliferation is a barrier to transplantation tolerance

Terapia de indução com alentuzumabe em receptores de transplante renal

The response of intestinal stem cells and epithelium after alemtuzumab administration

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