HISTOLOGIC CHARACTERIZATION OF THE IMMUNE RESPONSE TO RENAL ALLOGRAFTS IN PATIENTS RECEIVING AGGRESSIVE DEPLETIONAL INDUCTION PROTOCOLS

 

DE Kleinerl, LC Cendales2, DA Hale2, RB Mannon2, SJ Swanson2, AD Kirk2, lLaboratory of Pathology, NCI, Bethesda, MD, 20892 and 2Transplantation and Autoimmunity Branch, NIDDK, Bethesda, MD, 20892

 

Background. Acute cellular rejection of renal allografts is characterized by an immune response dominated and mediated by T -cells. Traditional immunosuppression prevents this response by inhibiting T-cell activation and function with the cost of significant side effects. We have explored the use of novel immunosuppressive protocols that couple transplantation with aggressive depletion of immune cells. In particular, we have used alemtuzimab (humanized anti-CD52) and rabbit antithymocyte globulin (RATG) with sirolimus monotherapy as methods of rapidly ablating the initial T-cell response to the graft. We summarize histologic findings made during episodes of acute rejection and compare these findings to episodes of acute rejection observed in patients treated on standard triple-drug immunosuppression protocols.

 

Design. All renal allograft biopsies performed on patients treated with alemtuzimab or RATG induction or with standard immunosuppression and diagnosed as showing borderline or acute allograft rejection were reviewed. Rejection was graded according to BANFF 97 criteria. Irnmunophenotyping was performed using antibodies to CD3, CD4, CD8, CD20, CD45, CD68, HLA-DR, perforin and granzyme B and was scored semiquantitatively on a scale from 0 to 6. Data was analyzed using post-hoc ANOVA and Kruskal-Wallis tests.

 

Results. A total of 70 biopsies on 49 patients were identified. BANFF 97 grading revealed a total of 33 borderline, 20 grade IA, 10 grade IB, 5 grade IIA and 2 grade IIB acute rejections.  All patients with at least grade IA rejection and patients on depletional protocols with histologic borderline rejection had renal dysfunction that responded to additional immunosuppression.  None of the biopsies had BK virus infection. The distribution of grades across the three protocols was not skewed (Chi square, p>0.1). The intensity of inflammation in acute rejection episodes revealed significant differences between patients on depletional protocols vs patients on standard therapy. In particular, the number of cells staining for CD45, CD20 and CD3 was less in patients on depletional protocols (p < 0.001,0.02, and 0.001 respectively). Infiltration by CD68 positive macrophages was greater in patients receiving alemtuzimab than those receiving standard therapy (p = 0.048). CD4 (+) cells (including both macrophages and lymphocytes) were reduced in patients receiving RATG as compared to patients receiving standard therapy (p = 0.002). Staining of tubular epithelium for HLA-DR was more extensive in patients receiving alemtuzimab than in either of the other protocols (p = 0.01). In general, patients who received RATG had changes that were intermediate between patients who received alemtuzimab and those on standard therapy.

 

Conclusion. Patients on aggressive depletional induction protocols had novel macrophage-rich, lymphocyte depleted reactions against the graft and patients receiving alemtuzimab had the most striking changes in the immune response. These findings highlight the possibility of mechanisms of rejection other than the standard T -cell mediated cellular immunity. In particular, the role of the macrophage as a potential initiator, mediator or effector cell in this process deserves further investigation.

 

 

 

HISTOLOGIC CHARACTERIZATION OF THE IMMUNE RESPONSE TO RENAL ALLOGRAFTS IN PATIENTS RECEIVING AGGRESSIVE DEPLETIONAL INDUCTION PROTOCOLS

 

DE Kleinerl, LC Cendales2, DA Hale2, RB Mannon2, SJ Swanson2, AD Kirk2, lLaboratory of Pathology, NCI, Bethesda, MD, 20892 and 2Transplantation and Autoimmunity Branch, NIDDK, Bethesda, MD, 20892

 

David E. Kleiner, M.D., Ph.D.

Laboratory of Pathology/NCI

Bldg 10, Room 2N212, MSC 1516

Bethesda, MD 20892

 

Tel: 301-594-2942

Fax: 301-480-9488

dkleiner@helix.nih.gov