Alloantigen Expression on Host Target Epithelium Inhibits Graft-Versus-Leukemia (GVL) Effects.
Authors: Asakura Shoji , Hashimoto Daigo , Matsuoka Ken-ichi , Sakoda Yukimi , Tanimoto Mitsune , Teshima Takanori 
Published: October 2019

We previously demonstrated that alloantigen expression on host target epithelium is not necessary but augment acute GVHD (Nat Med 2002). Here, we tested the role of alloantigen expression on host target epithelium on the GVL effect. We created BM chimeras, [B6 → C3H.Sw] where only host hematopoietic cells express multiple minor histocompatibility antigens (mHAs) allogeneic to the donors but not on host target epithelium. Identically treated [B6 → B6] chimeras were created as controls where both hematopoietic and target cells express mHAs allogeneic to the donors. Four month later, these chimeras were reirradiated and were injected with 5×106 BM and 1×106 CD8 T cells harvested from C3H.Sw donors. Acute GVHD developed in [B6 → C3H.Sw] chimeras but was less severe in these chimeras than controls (Table). Next, animals were transplanted, as above, with the addition of 2500 B6-derived EL4 thymoma to the donor inoculum. The cause of death was determined by postmortem examination to be either GVHD or leukemia (presence of hepatic and/or splenic nodules). All [B6 → B6] recipients of C3H.Sw CD8+ cells died from leukemia, although their survival time was significantly prolonged compared to syngeneic controls (P<.01). Surprisingly, [B6 → C3H.Sw] chimeras displayed more potent GVL effects than controls (Table), in spite of reduced GVHD in these chimeras. Similar results were obtained in the other sets of chimeras [DBA → Balb/c] when injected with BM and T cells isolated from Balb/c donors together with DBA-derived P815 mastocytoma and [Balb/c → DBA] when injected with BM and T cells isolated from DBA donors and Balb/c-derived A20 lymphoma. These animals displayed more potent GVL effects compared to control chimeras (Table). To elucidate the mechanisms of this superior GVL effect in these chimeras, analysis of the spleen was performed 3 weeks after BMT. Expansion and activation of donor CD8+ T cells were greater in [B6 → C3H.Sw] recipients than those in [B6 → B6] recipients in spleens (P<.05). Thus, alloantigens expressed on host antigen-presenting cells stimulate host-reactive T cells but in the absence of alloantigen expression on host epithelium contraction of host-reactive T cells may be impaired, resulting in a superior GVL effect. These results provides a complete picture of the role of alloantigen expression on host epithelium in allogeneic hematopoietic cell transplantation; alloantigen expression on host target cells i) does not always necessary to induce acute GVHD, ii) augment GVHD, and iii) suppress GVL effects. These imply that allogeneic cellular therapy targeting at mHA preferentially expressed on hematopoietic cells may induce potent GVL effects while inducing less severe GVHD.

Donor Recipients GVHD score (d21) GVHD mortality (d50) Leukemia mortality (d50) *P<.05. **not examined B6 CD8 [B6 → B6] 1.0 +/− 0.4 0% 100% C3H.Sw CD8 [B6 → B6] 3.7 +/− 0.3 33% 95% C3H.Sw TCD [B6 → C3H.Sw] NE** 0% 100% C3H.Sw CD8 [B6 → C3H.Sw] 2.1 +/− 0.4* 0%* 69%* Balb/c TCD [DBA → DBA] 0.2 +/− 0.3 NE** 100% Balb/c T [DBA→ DBA] 3.2 +/− 0.6 NE** 60% Balb/c TCD [DBA→ Balb/c] NE** NE** 100% Balb/c T [DBA→ Balb/c] 1.3 +/− 0.3* NE** 10%* DBA TCD [Balb/c→ Balb/c] 0.0 +/− 0.0 NE** 100% DBA T [Balb/c→ DBA] 1.8 +/− 0.6 NE** 100% DBA TCD [Balb/c→ Balb/c] NE** NE** 100% DBA T [Balb/c→ DBA] 0.8 +/− 0.3 NE** 30%*